阅读说明：本技术 一种唑来膦酸中间体化合物 (Zoledronic acid intermediate compound ) 是由 翟立海 杨宇 谢印杰 徐杰 于 2019-09-28 设计创作，主要内容包括：本发明属于医药合成技术领域,具体涉及一种唑来膦酸中间体化合物。本发明以2,2-双取代乙酸酯和咪唑为起始原料,经过取代反应、水解反应合成2,2-咪唑乙酸盐酸盐中间体,该方法原料简单易得,反应条件温和,操作过程简便,经济环保；利用该中间体化合物制备的唑来膦酸收率可达到85.27％,且无双膦酸杂质,纯度高达99.8％以上。(The invention belongs to the technical field of medicine synthesis, and particularly relates to a zoledronic acid intermediate compound. The 2, 2-disubstituted acetate and imidazole are used as initial raw materials, and the intermediate of 2, 2-imidazole acetate is synthesized through substitution reaction and hydrolysis reaction, so that the method has the advantages of simple and easily obtained raw materials, mild reaction conditions, simple and convenient operation process, economy and environmental protection; the yield of the zoledronic acid prepared by the intermediate compound can reach 85.27%, no diphosphonic acid impurity exists, and the purity is as high as more than 99.8%.)

1. A zoledronic acid intermediate compound of formula I:

2. a process for preparing zoledronic acid intermediate compound i as claimed in claim 1, wherein SM-1 is reacted with SM-2 to obtain SM-3, which is hydrolyzed and salified to obtain zoledronic acid intermediate compound i, the reaction formula is as follows:

wherein X and Y are respectively and independently selected from Cl, Br or I; r is C_1-5An alkyl group.

3. The preparation method according to claim 2, characterized by comprising the following steps:

1) in an aprotic solvent containing alkali, carrying out reflux reaction on a compound SM-1 and a compound SM-2 under the action of a catalyst, and obtaining a compound SM-3 after the reaction is finished;

2) and carrying out reflux reaction on the compound SM-3 and concentrated hydrochloric acid, and finishing hydrolysis and salt forming reaction to obtain a compound I.

4. The preparation method of claim 3, wherein the base in step 1) is one or a combination of potassium carbonate, sodium carbonate, triethylamine and sodium hydroxide; the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, hexadecyltrimethylammonium bromide, iodine and potassium iodide; the aprotic solvent is one or the combination of acetonitrile, tetrahydrofuran, 1, 4-dioxane, dimethylformamide and dimethyl sulfoxide.

5. The preparation method according to claim 3, wherein the molar ratio of the compound SM-1, the compound SM-2 and the catalyst in step 1) is 1: 0.2-0.4: 0.002-0.005.

6. The preparation method according to claim 3, wherein the charging molar ratio of the compound SM-1 to the base in the step 1) is 1: 1-4.

7. Use of zoledronic acid intermediate compound I as described in claim 1 for the preparation of zoledronic acid.

8. The method for preparing zoledronic acid by using the zoledronic acid intermediate compound I as claimed in claim 1, is characterized in that the zoledronic acid intermediate compound I is subjected to temperature-controlled reaction with phosphoric acid and phosphorus trichloride, and after the reaction is finished, the zoledronic acid is hydrolyzed to obtain zoledronic acid, and the synthetic route is as follows:

9. the method according to claim 8, wherein the feeding molar ratio of the compound I, the phosphorus trichloride and the phosphoric acid is 1: 3-5: 3 to 5.

10. The method according to claim 8, wherein the temperature-controlled reaction temperature is 70-100 ℃; the reaction solvent is one or the combination of 1, 4-dioxane, toluene and trifluoroacetic acid.

Technical Field

The invention belongs to the technical field of medicine synthesis, and particularly relates to a zoledronic acid intermediate compound.

Background

Zoledronic Acid (Zoledronic Acid), having the chemical name 1-hydroxy-2- ((1-imidazolyl) -ethylene) -1, 1-bisphosphonic Acid, is a heterocyclic third-generation bisphosphonate drug developed by Novartis, Switzerland, was first approved in Canada under the name Zomet in 2000 and subsequently approved in more than 80 countries or regions, such as the European Union, the United states, and the like. Zoledronic acid can be used for treating Hypercalcemia (HCM) caused by malignant tumor and bone metastasis of multiple myeloma and solid tumor, has therapeutic effect on HCM caused by malignant tumor, late stage tumor metastasis and osteitis deformans, can reduce occurrence of bone related events, relieve symptoms, improve quality of life, and is expected to be used for treating osteoporosis, and the action mechanism of the zoledronic acid is to inhibit bone resorption to reduce release of bone matrix growth factor or to inhibit cancer cells from adhering to bone matrix. Compared with other similar medicines, the zoledronic acid has the advantages of good curative effect, high safety, convenient administration, small dosage and the like, and is the only bisphosphonate medicine approved by the FDA for treating the bone metastasis of the solid tumor at present. The chemical structural formula is as follows:

according to the reported patent literature information, imidazole and halogenated acetate are used as raw materials in the synthesis process of zoledronic acid, such as US2010130746A1, US4939130A, US5510517A, WO2005063717, WO03093282, WO2006134603 and the like, imidazole and halogenated acetate are hydrolyzed after reaction to obtain imidazole acetic acid, and then the imidazole acetic acid reacts with phosphorus trichloride/phosphorus oxychloride and phosphoric acid/phosphorous acid to obtain zoledronic acid after hydrolysis, and the method can generate bisphosphonate impurities (formula V), influences the product purity, and uses chlorobenzene which has great pollution to human bodies and the environment as a solvent; in the Chinese patent application CN1693308A, imidazole and halogenated acetonitrile are used as raw materials, and the halogenated acetonitrile is toxic, so that nitrile compounds with high toxicity are likely to be generated in the reaction process, and high requirements are provided for the protection of production personnel and the treatment of three wastes.

In J.chem.Soc.,1932, 1806-one 1812, chloroacetic ester and aminoacetal are used as starting materials, imidazole acetate is prepared through multi-step synthesis, and after reaction with phosphorus trichloride and phosphoric acid, the product zoledronic acid is obtained through hydrolysis. The method has the advantages of difficult raw material source, complex reaction operation and lower industrial implementation foundation.

WO2005066188Al takes imidazole, chloracetyl chloride and benzyl alcohol as raw materials to synthesize benzyl-1-imidazole acetate, imidazole acetic acid is obtained after debenzylation, and then the imidazole acetic acid reacts with phosphorus trichloride and phosphoric acid to obtain zoledronic acid after hydrolysis. The method has a long synthesis period, requires at least 13 hours in the first step of reaction, and the industrial production value is still to be improved.

Eur.J.Inorg.chem.,1960,93: 2804. 2809 synthesizes imidazole acetic acid hydrochloride by using 1- (trimethylsilane) imidazole as a starting material, wherein the yield of imidazole acetic acid is 63%, but the cost of the raw materials 1- (trimethylsilane) imidazole and trimethylsilyl chloroacetate is high, so that the industrial production is difficult to realize; the chem.pharm.Bull, 1983,31(4): 1213-; in the literature, "improvement of synthesis process of sodium zoledronate" (chemical reagent, 2009,31(5), 383-385), ionic liquid is used as a reaction medium, and although the yield of the obtained zoledronic acid is high, the preparation method of the ionic liquid is complex and is not suitable for large-scale production.

Therefore, it is still a problem to be solved at present to explore a process route for synthesizing zoledronic acid, which is simple and convenient to operate, economic and environment-friendly, short in production period, high in yield and more suitable for industrial production.

Disclosure of Invention

Aiming at the problems of low environmental protection, long reaction period, bisphosphonate impurity content and the like in the existing zoledronic acid synthesis process, the invention provides a zoledronic acid intermediate compound I and a preparation method thereof; the method has the advantages of simple and easily obtained raw materials, mild reaction conditions and simple and convenient operation process; the zoledronic acid prepared by the compound has higher purity and yield, and does not contain bisphosphonate impurities.

A zoledronic acid intermediate compound of formula I:

a preparation method of zoledronic acid intermediate compound shown in formula I comprises the following steps of reacting SM-1 with SM-2 to obtain SM-3, and hydrolyzing and salifying to obtain zoledronic acid intermediate compound I, wherein the reaction formula is as follows:

wherein X and Y are respectively and independently selected from Cl, Br or I; r is C_1-5An alkyl group.

A preparation method of a zoledronic acid intermediate compound I comprises the following steps:

1) in an aprotic solvent containing alkali, carrying out reflux reaction on a compound SM-1 and a compound SM-2 under the action of a catalyst, and obtaining a compound SM-3 after the reaction is finished;

2) and carrying out reflux reaction on the compound SM-3 and concentrated hydrochloric acid, and finishing hydrolysis and salt forming reaction to obtain a compound I.

Preferably, the preparation method of the zoledronic acid intermediate compound I comprises the following steps:

1) sequentially adding a compound SM-1, alkali and a catalyst into an aprotic solvent, heating, stirring, refluxing, simultaneously dropwise adding a compound SM-2, and obtaining an oily liquid compound SM-3 after the reaction is finished;

2) adding concentrated hydrochloric acid into the compound SM-3, heating, stirring, refluxing, performing rotary drying after the reaction is finished, pulping, washing and drying to obtain a white solid compound I.

Preferably, the aprotic solvent in step 1) is one or a combination of acetonitrile, tetrahydrofuran, 1, 4-dioxane, dimethylformamide and dimethyl sulfoxide, wherein acetonitrile is particularly preferred.

Preferably, the feeding molar ratio of the compound SM-1, the compound SM-2 and the catalyst in the step 1) is 1: 0.2-0.4: 0.002-0.005, and particularly preferably 1:0.35: 0.003.

Preferably, the feeding molar ratio of the compound SM-1 to the alkali in the step 1) is 1: 1-4.

Preferably, the base in step 1) is one or a combination of potassium carbonate, sodium carbonate, triethylamine and sodium hydride, wherein triethylamine is particularly preferred.

Preferably, the catalyst in step 1) is one of tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, hexadecyltrimethylammonium bromide, iodine and potassium iodide, wherein iodine is particularly preferred.

In a preferable scheme, the post-treatment step in the step 1) is to perform filtration after the reaction is finished, pulp and wash a filter cake by using acetonitrile, remove the solvent by reduced pressure rotary evaporation, then add absolute ethyl alcohol, stir, filter and spin-dry to obtain the oily liquid compound SM-3.

Preferably, the mass-to-volume ratio of the compound SM-3 to the concentrated hydrochloric acid in the step 2) is 1:1 to 3 g/ml, and particularly preferably 1: 2, g/ml.

Preferably, the solvent used in the beating washing in the step 2) is absolute ethyl alcohol.

The application of the zoledronic acid intermediate compound I in preparing zoledronic acid.

A method for preparing zoledronic acid by using a zoledronic acid intermediate compound I is characterized in that the zoledronic acid intermediate compound I, phosphoric acid and phosphorus trichloride are subjected to temperature control reaction, and after the reaction is finished, hydrolysis is carried out to obtain zoledronic acid, wherein the synthetic route is as follows:

the method for preparing the zoledronic acid by using the zoledronic acid intermediate compound I comprises the following steps: adding the compound I into a reaction solvent, adding phosphoric acid after completely dissolving, heating, preserving heat, dropwise adding phosphorus trichloride, controlling the temperature for reaction, adding a hydrochloric acid solution after the reaction is finished, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, crystallizing, performing suction filtration, and drying to obtain the zoledronic acid.

Preferably, the feeding molar ratio of the compound I, phosphorus trichloride and phosphoric acid is 1: 3-5, and particularly preferably 1:4: 4.

Preferably, the temperature of the heat preservation and temperature control reaction is 70-100 ℃.

Preferably, the reaction solvent is one or a combination of 1, 4-dioxane, toluene and trifluoroacetic acid, wherein toluene is particularly preferred.

Preferably, the phosphoric acid is 85% phosphoric acid.

Preferably, the crystallization method is to add a crystallization solvent into the concentrated solution and stir for crystallization.

Preferably, the crystallization solvent is one of acetone, ethanol, methanol and water, wherein ethanol is particularly preferred.

In a preferable scheme, the refining step of the zoledronic acid comprises the steps of adding the zoledronic acid obtained in the previous step into purified water, heating to reflux, adding activated carbon for decoloring after the zoledronic acid is completely dissolved, carrying out suction filtration while the zoledronic acid is hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and drying to obtain the zoledronic acid.

Preferably, the decoloring time is 20-40 min.

Structure confirmation of compound I:

single crystal diffraction detection:

the X-ray single crystal diffraction test instrument and the test conditions used by the compound I of the invention are as follows: chemistry XtaLAB Synergy X-ray single crystal diffractometer; the method comprises the steps of collecting data by using a light source copper target, the temperature is 293K, the voltage is 50kv and the current is 1mA, and adopting Cu-Kalpha target ray scanning, wherein the collecting method is an orthogonal method. The stereo structure of the single crystal molecule is shown in figure 1, and the crystallographic data are shown in table 1.

TABLE 1 crystallographic data for Compound I

Compared with the prior art, the invention has the following technical effects:

1. the invention provides a novel zoledronic acid intermediate compound, which is simple and easy to synthesize, avoids using halogenated acetonitrile, is economic and environment-friendly, and improves the safety of operation.

2. The method breaks through the limitation reported in the past, and the zoledronic acid is prepared by taking 2, 2-bisimidazolyl acetic acid hydrochloride as an intermediate, so that the yield can reach 85.27%, the purity is as high as more than 99.8%, and no diphosphonate impurities exist.

Drawings

FIG. 1: ORTEP diagram of compound I2, 2-bisimidazolylacetic acid hydrochloride.

Detailed Description

The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.

Example 1

Sequentially adding imidazole (68.00g, 1mol), potassium carbonate (276.43g, 2mol) and tetrabutylammonium bromide (0.97g, 0.003mol) into acetonitrile (1000ml), stirring and refluxing, simultaneously dropwise adding ethyl dichloroacetate (54.95g, 0.35mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by using acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and carrying out rotary drying to obtain 72.45g of oily liquid compound 2, 2-ethyl imidazolium acetate with the yield of 93.98%;

adding concentrated hydrochloric acid (215ml) into 2, 2-imidazole ethyl acetate (72.45g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, then adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 73.11g of a white solid compound, namely 2, 2-imidazole acetate hydrochloride, wherein the yield is 97.21%;

adding 73.11g of 2, 2-imidazole acetic acid hydrochloride into 300ml of toluene, adding 125.34g of 85% phosphoric acid after complete dissolution, heating to 90 ℃, preserving heat, and dropwise adding 175.65g of PCl₃Controlling the temperature to react at 90 ℃, adding 300ml of HCl solution with the concentration of 9mol/L after the reaction is finished, heating to reflux, and finishing the reflux reactionCooling to room temperature after the reaction, concentrating under reduced pressure, adding 500ml ethanol into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 81.21g of zoledronic acid, wherein the yield is 93.34%.

Total yield 85.27%, purity 99.93%, and diphosphate impurity 0%.

Example 2

Sequentially adding imidazole (68.00g, 1mol), triethylamine (101.12g, 1mol) and iodine (1.27g, 0.005mol) into 1, 4-dioxane (1000ml), stirring and refluxing, simultaneously dropwise adding ethyl dichloroacetate (31.4g, 0.2mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and carrying out rotary drying to obtain 39.83g of oily liquid compound ethyl 2, 2-imidazoleacetate, wherein the yield is 90.42%;

adding concentrated hydrochloric acid (80ml) into 2, 2-imidazole ethyl acetate (39.83g), stirring and refluxing, after the reaction is finished, carrying out spin drying, adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 39.92g of white solid compound 2, 2-imidazole acetate hydrochloride, wherein the yield is 96.55%;

39.92g of 2, 2-imidazole acetic acid hydrochloride is added into 300ml of trifluoroacetic acid, 85.55g of 85% phosphoric acid is added after complete dissolution, the temperature is raised to 70 ℃, heat preservation is carried out, 71.93g of PCl is dripped₃Controlling the temperature to react at 70 ℃, after the reaction is finished, adding 300ml of HCl solution with the concentration of 9mol/L, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of acetone into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 20min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 43.23g of zoledronic acid, wherein the yield is 91.00%.

Total yield 79.44%, purity 99.89%, and diphosphate impurity 0%.

Example 3

Sequentially adding imidazole (68.00g, 1mol), sodium carbonate (423.96, 4mol) and hexadecyl trimethyl ammonium bromide (0.73g, 0.002mol) into dimethyl sulfoxide (1000ml), stirring and refluxing, simultaneously dropwise adding ethyl dichloroacetate (62.80g, 0.4mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 79.44g of oily liquid compound 2, 2-ethyl imidazolate, wherein the yield is 90.17%;

adding concentrated hydrochloric acid (318ml) into 2, 2-imidazole ethyl acetate (79.44g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, then adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 79.98g of a white solid compound, namely 2, 2-imidazole acetate hydrochloride, wherein the yield is 96.99%;

adding 79.98g of 2, 2-imidazole acetic acid hydrochloride into 300ml of 1, 4-dioxane, adding 102.80g of 85% phosphoric acid after complete dissolution, heating to 100 ℃, preserving heat, and dropwise adding 240.20g of PCl₃Controlling the temperature to react at 100 ℃, adding 300ml of HCl solution with the concentration of 9mol/L after the reaction is finished, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of methanol into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 40min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 85.15g of zoledronic acid, wherein the yield is 89.46%.

The total yield is 78.24%, the purity is 99.87%, and the impurity of the diphosphate is 0%.

Example 4

Sequentially adding imidazole (68.00g, 1mol), sodium hydride (24.00g, 1mol) and benzyltriethylammonium chloride (0.68g, 0.003mol) into 1000ml of dimethylformamide, stirring and refluxing, simultaneously dropwise adding ethyl dichloroacetate (47.10g, 0.3mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by using acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 61.05g of oily liquid compound ethyl 2, 2-imidazoleacetate, wherein the yield is 92.40%;

adding concentrated hydrochloric acid (183ml) into 2, 2-imidazole ethyl acetate (61.05g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, then adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 61.50g of a white solid compound, namely 2, 2-imidazole acetate hydrochloride, wherein the yield is 97.04%;

adding 61.50g of 2, 2-imidazole acetic acid hydrochloride into 300ml of toluene, adding 131.79g of 85% phosphoric acid after complete dissolution, heating to 80 ℃, preserving heat, and dropwise adding 147.76g of PCl₃Controlling the temperature to react at 80 ℃, after the reaction is finished, adding 300ml of HCl solution with the concentration of 9mol/L, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of purified water into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 67.71g of zoledronic acid, wherein the yield is 92.52%.

Total yield 82.96%, purity 99.91%, and diphosphate impurity 0%.

Example 5

Sequentially adding imidazole (68.00g, 1mol), potassium carbonate (276.43g, 2mol) and tetrabutylammonium bromide (0.97g, 0.003mol) into acetonitrile (1000ml), stirring and refluxing, simultaneously dropwise adding ethyl dichloroacetate (23.55g, 0.15mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by using acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 29.51g of oily liquid compound ethyl 2, 2-imidazoleacetate, wherein the yield is 89.32%;

adding concentrated hydrochloric acid (89ml) into 2, 2-imidazole ethyl acetate (29.51g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, then adding absolute ethyl alcohol, pulping, washing (100ml multiplied by 2), and drying to obtain 29.77g of a white solid compound, namely 2, 2-imidazole acetate hydrochloride, wherein the yield is 97.18%;

adding 29.77g of 2, 2-imidazole acetic acid hydrochloride into 300ml of toluene, adding 25.52g of 85% phosphoric acid after complete dissolution, heating to 90 ℃, preserving heat, and dropwise adding 35.76g of PCl₃Controlling the temperature to react at 90 ℃, after the reaction is finished, adding 300ml of HCl solution with the concentration of 9mol/L, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of ethanol into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 31.44g of zoledronic acid, wherein the yield is 88.74%.

Total yield 77.03%, purity 99.78%, and diphosphate impurity 0%.

Example 6

Sequentially adding imidazole (68.00g, 1mol), potassium carbonate (276.43g, 2mol) and dodecyl dimethyl benzyl ammonium chloride (1.02g, 0.003mol) into acetonitrile (1000ml), stirring and refluxing, simultaneously dropwise adding ethyl dichloroacetate (54.95g, 0.35mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by using acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 68.89g of oily liquid compound ethyl 2, 2-imidazoleacetate, wherein the yield is 89.37%;

adding concentrated hydrochloric acid (207ml) into 2, 2-imidazole ethyl acetate (68.89g), stirring and refluxing, after the reaction is finished, carrying out spin drying, adding absolute ethyl alcohol, pulping, washing (100ml multiplied by 2), and drying to obtain 69.41g of a white solid compound, namely 2, 2-imidazole acetate hydrochloride, wherein the yield is 97.06%;

69.41g of 2, 2-imidazole acetic acid hydrochloride is added into 300ml of toluene, 119.00g of 85% phosphoric acid is added after complete dissolution, the temperature is heated to 90 ℃, heat preservation is carried out, 166.76g of PCl is dripped₃Controlling the temperature to react at 90 ℃, after the reaction is finished, adding 300ml of HCl solution with the concentration of 9mol/L, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of ethanol into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; to the resulting zoledronic acidAdding 2000ml of purified water into the crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature while stirring, crystallizing, carrying out suction filtration, and carrying out air drying at 40 ℃ under normal pressure to obtain 77.05g of zoledronic acid with the yield of 93.28%.

The total yield is 80.91%, the purity is 99.81%, and the impurity content of the diphosphate is 0%.

Example 7

Sequentially adding imidazole (68.00g, 1mol), potassium carbonate (276.43g, 2mol) and tetrabutylammonium bromide (0.97g, 0.003mol) into acetonitrile (1000ml), stirring and refluxing, simultaneously dropwise adding n-butyl dibromoacetate (95.88g, 0.35mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by using acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 79.33g of compound 2, 2-n-butyl imidazoleacetate, wherein the yield is 91.30%;

adding concentrated hydrochloric acid (238ml) into 2, 2-imidazole n-butyl acetate (79.33g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, adding absolute ethyl alcohol, pulping, washing (100ml multiplied by 2), drying, and obtaining 71.00g of white solid compound 2, 2-imidazole acetate hydrochloride with the yield of 97.18%;

71.00g of 2, 2-imidazole acetic acid hydrochloride is added into 300ml of toluene, 121.72g of 85 percent phosphoric acid is added after complete dissolution, the temperature is heated to 90 ℃, the temperature is kept, 170.58g of PCl is dripped₃Controlling the temperature to react at 90 ℃, after the reaction is finished, adding 300ml of HCl solution with the concentration of 9mol/L, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of ethanol into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 78.82g of zoledronic acid, wherein the yield is 93.29%.

Total yield 82.77%, purity 99.90%, and biphosphate impurity 0%.

Example 8

Sequentially adding imidazole (68.00g, 1mol), potassium carbonate (414.63g, 3mol) and tetrabutylammonium chloride (1.11g, 0.004mol) into 1000ml of tetrahydrofuran, stirring and refluxing, simultaneously dropwise adding ethyl dibromoacetate (73.77g, 0.3mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by using acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove the solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 60.69g of oily liquid compound ethyl 2, 2-imidazoleacetate, wherein the yield is 91.85%;

adding concentrated hydrochloric acid (151ml) into 2, 2-imidazole ethyl acetate (60.69g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, then adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 60.97g of white solid compound 2, 2-imidazole acetate hydrochloride, wherein the yield is 96.77%;

60.97g of 2, 2-imidazole acetic acid hydrochloride is added into 300ml of trifluoroacetic acid, 78.39g of 85% phosphoric acid is added after complete dissolution, the temperature is heated to 95 ℃, heat preservation is carried out, 109.86g of PCl is dripped₃Carrying out temperature-controlled reaction at 95 ℃, after the reaction is finished, adding 300ml of 9mol/L HCl solution, heating to reflux, cooling to room temperature after the reflux reaction is finished, carrying out reduced pressure concentration, adding 500ml of ethanol into the concentrated solution, crystallizing, carrying out suction filtration, and carrying out air drying at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 66.60g of zoledronic acid, wherein the yield is 91.79%.

Total yield 81.59%, purity 99.89%, and diphosphate impurity 0%.

Example 9

Sequentially adding imidazole (68.00g, 1mol), triethylamine (101.19g, 1mol) and potassium iodide (0.332g, 0.002mol) into a mixed solution of acetonitrile (500ml) and 1, 4-dioxane (500ml), stirring and refluxing, simultaneously dropwise adding diiodo ethyl acetate (118.96g, 0.35mol), filtering after the reflux reaction is finished, pulping and washing a filter cake with acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove the solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering, and carrying out rotary drying to obtain 70.40g of oily liquid compound 2, 2-imidazole ethyl acetate, wherein the yield is 91.32%;

adding concentrated hydrochloric acid (211ml) into 2, 2-imidazole ethyl acetate (70.40g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, then adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 70.36g of a white solid compound, namely 2, 2-imidazole acetate hydrochloride, wherein the yield is 96.28%;

adding 70.36g of 2, 2-imidazole acetic acid hydrochloride into 300ml of toluene, adding 120.62g of 85% phosphoric acid after complete dissolution, heating to 90 ℃, preserving heat, and dropwise adding 169.04g of PCl₃Controlling the temperature to react at 90 ℃, after the reaction is finished, adding 300ml of HCl solution with the concentration of 9mol/L, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of acetone into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 77.17g of zoledronic acid, wherein the yield is 92.16%.

The total yield is 81.03 percent, the purity is 99.86 percent, and the impurity of the diphosphate is 0 percent.

Example 10

Sequentially adding imidazole (68.00g, 1mol), sodium hydride (24g, 1mol) and benzyltriethylammonium chloride (1.14g, 0.005mol) into dimethyl sulfoxide (1000ml), stirring and refluxing, simultaneously dropwise adding 2-bromo-2-chloroacetic acid ethyl ester (60.43g, 0.3mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake with acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding methanol (2000ml), stirring, filtering and spin-drying to obtain 59.18g of oily liquid compound ethyl 2, 2-imidazoleacetate, wherein the yield is 89.56%;

adding concentrated hydrochloric acid (237ml) into 2, 2-imidazole ethyl acetate (59.18g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, then adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 59.52g of a white solid compound, namely 2, 2-imidazole acetate hydrochloride, wherein the yield is 96.88%;

adding 59.52g 2, 2-imidazole acetic acid hydrochloride into 300ml 1, 4-dioxane, adding 127.55g 85% phosphoric acid after completely dissolving, heating to 100 deg.C, keeping the temperature, and dripping 178.75g PCl₃Controlling the temperature to react at 100 ℃, adding 300ml of HCl solution with the concentration of 9mol/L after the reaction is finished, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of purified water into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 63.68g of zoledronic acid, wherein the yield is 89.90%.

The total yield is 78.00%, the purity is 99.82%, and the impurity content of the diphosphate is 0%.

Example 11

Sequentially adding imidazole (68.00g, 1mol), sodium carbonate (317.97g, 3mol) and hexadecyl trimethyl ammonium bromide (0.73g, 0.002mol) into acetonitrile (1000ml), stirring and refluxing, simultaneously dropwise adding isopropyl dichloroacetate (34.20g, 0.2mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by using acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 42.60g of oily liquid compound 2, 2-imidazole isopropyl acetate, wherein the yield is 90.93%;

adding concentrated hydrochloric acid (128ml) into isopropyl 2, 2-imidazole acetate (42.60g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 40.39g of a white solid compound, namely 2, 2-imidazole acetate hydrochloride, wherein the yield is 97.14%;

40.39g of 2, 2-imidazole acetic acid hydrochloride is added into 300ml of trifluoroacetic acid, 69.24g of 85 percent phosphoric acid is added after complete dissolution, the temperature is heated to 90 ℃, heat preservation is carried out, 121.30g of PCl is dripped₃Controlling the temperature to react at 90 ℃, after the reaction is finished, adding 300ml of HCl solution with the concentration of 9mol/L, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of acetone into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of active carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, and cooling the filtrate to room under stirringThe mixture is warmed, crystallized, filtered, and dried by blowing at 40 ℃ and normal pressure to obtain 42.82g of zoledronic acid with the yield of 89.09%.

Total yield 78.69%, purity 99.79%, and diphosphate impurity 0%.

Example 12

Sequentially adding imidazole (68.00g, 1mol), potassium carbonate (552.84g, 4mol) and tetrabutylammonium chloride (1.11g, 0.004mol) into 1000ml of tetrahydrofuran, stirring and refluxing, simultaneously dropwise adding methyl dichloroacetate (35.74g, 0.25mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by using acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove the solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 47.44g of oily liquid compound 2, 2-methyl imidazolate, wherein the yield is 92.00%;

adding concentrated hydrochloric acid (95ml) into 2, 2-imidazole methyl acetate (47.44g), stirring and refluxing, after the reaction is finished, carrying out spin drying, adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 50.57g of white solid compound 2, 2-imidazole acetate hydrochloride, wherein the yield is 96.16%;

50.57g of 2, 2-imidazole acetic acid hydrochloride is added into 300ml of toluene, 86.70g of 85% phosphoric acid is added after complete dissolution, the temperature is heated to 95 ℃, heat preservation is carried out, 121.50g of PCl is added dropwise₃Carrying out temperature-controlled reaction at 95 ℃, after the reaction is finished, adding 300ml of 9mol/L HCl solution, heating to reflux, cooling to room temperature after the reflux reaction is finished, carrying out reduced pressure concentration, adding 500ml of ethanol into the concentrated solution, crystallizing, carrying out suction filtration, and carrying out air drying at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 55.28g of zoledronic acid, wherein the yield is 91.86%.

The total yield is 81.27%, the purity is 99.90%, and the impurity content of the diphosphate is 0%.

Example 13

Sequentially adding imidazole (68.00g, 1mol), potassium carbonate (276.43g, 2mol) and tetrabutylammonium bromide (0.97g, 0.003mol) into acetonitrile (1000ml), stirring and refluxing, simultaneously dropwise adding methyl dichloroacetate (50.04g, 0.35mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by using acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and carrying out rotary drying to obtain 67.75g of oily liquid compound methyl 2, 2-imidazoleacetate, wherein the yield is 93.85%;

adding concentrated hydrochloric acid (204ml) into 2, 2-imidazole methyl acetate (67.75g), stirring and refluxing, after the reaction is finished, carrying out spin drying, adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 72.94g of a white solid compound, namely 2, 2-imidazole acetate hydrochloride, wherein the yield is 97.12%;

adding 72.94g of 2, 2-imidazole acetic acid hydrochloride into 300ml of toluene, adding 125.05g of 85% phosphoric acid after complete dissolution, heating to 90 ℃, preserving heat, and dropwise adding 175.24g of PCl₃Controlling the temperature to react at 90 ℃, after the reaction is finished, adding 300ml of HCl solution with the concentration of 9mol/L, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of ethanol into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 81.04g of zoledronic acid, wherein the yield is 93.36%.

Total yield 85.09%, purity 99.91%, and diphosphate impurity 0%.

Example 14

Sequentially adding imidazole (68.00g, 1mol), potassium carbonate (276.43g, 2mol) and tetrabutylammonium bromide (0.32g, 0.001mol) into acetonitrile (1000ml), stirring and refluxing, simultaneously dropwise adding methyl dichloroacetate (64.33g, 0.45mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by using acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 81.18g of oily liquid compound methyl 2, 2-imidazoleacetate, wherein the yield is 87.47%;

adding concentrated hydrochloric acid (82ml) into 2, 2-imidazole methyl acetate (81.18g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, then adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 85.01g of white solid compound 2, 2-imidazole acetate hydrochloride, wherein the yield is 94.46%;

85.01g of 2, 2-imidazole acetic acid hydrochloride is added into 300ml of toluene, 145.74g of 85% phosphoric acid is added after complete dissolution, the temperature is heated to 90 ℃, heat preservation is carried out, 204.24g of PCl is added dropwise₃Controlling the temperature to react at 90 ℃, after the reaction is finished, adding 300ml of HCl solution with the concentration of 9mol/L, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of ethanol into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 94.39g of zoledronic acid, wherein the yield is 93.30%.

The total yield is 77.09%, the purity is 99.80%, and the impurity of the diphosphate is 0%.

Example 15

Sequentially adding imidazole (68.00g, 1mol), triethylamine (101.19g, 1mol) and tetrabutylammonium bromide (0.97g, 0.003mol) into 1, 4-dioxane (1000ml), stirring and refluxing, simultaneously dropwise adding methyl dibromoacetate (69.56g, 0.3mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 57.71g of oily liquid compound methyl 2, 2-imidazoleacetate, wherein the yield is 93.27%;

adding concentrated hydrochloric acid (175ml) into 2, 2-imidazole methyl acetate (57.71g), stirring and refluxing, after the reaction is finished, carrying out spin drying, adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 62.06g of white solid compound 2, 2-imidazole acetate hydrochloride, wherein the yield is 97.01%;

62.06g of 2, 2-imidazole acetic acid hydrochloride is added into 300ml of 1, 4-dioxane, 132.99g of 85% phosphoric acid is added after complete dissolution, the temperature is heated to 90 ℃, the temperature is kept, and 186.38g of PCl is dropwise added₃Reacting at 90 deg.C, adding 300ml HCl solution with concentration of 9mol/L, heating to reflux, cooling to room temperature after reflux reaction, concentrating under reduced pressure, adding into concentrated solution500ml of ethanol, crystallization, suction filtration and normal pressure blast drying at 40 ℃ to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 66.32g of zoledronic acid, wherein the yield is 89.80%.

The total yield is 81.25%, the purity is 99.87%, and the impurity of the diphosphate is 0%.

Example 16

Sequentially adding imidazole (68.00g, 1mol), sodium hydride (48.00g, 2mol) and benzyltriethylammonium chloride (0.68g, 0.003mol) into dimethylformamide (1000ml), stirring and refluxing, simultaneously dropwise adding dichloroacetic acid amyl ester (89.58g, 0.45mol), after the reflux reaction is finished, filtering, pulping and washing a filter cake by acetonitrile (300ml multiplied by 3), combining organic phases, carrying out reduced pressure rotary evaporation to remove a solvent, then adding absolute ethyl alcohol (2000ml), stirring, filtering and spin-drying to obtain 105.67g of oily liquid compound 2, 2-imidazoleacetic acid amyl ester, wherein the yield is 89.54%;

adding concentrated hydrochloric acid (530ml) into 2, 2-imidazole acetic acid amyl ester (105.67g), stirring and refluxing, after the reaction is finished, carrying out spin-drying, then adding absolute ethyl alcohol, pulping and washing (100ml multiplied by 2), and drying to obtain 87.36g of a white solid compound, namely 2, 2-imidazole acetate hydrochloride, wherein the yield is 94.83%;

adding 87.36g of 2, 2-imidazole acetic acid hydrochloride into 300ml of toluene, adding 112.33g of 85% phosphoric acid after complete dissolution, heating to 100 ℃, preserving heat, and dropwise adding 157.42g of PCl₃Controlling the temperature to react at 100 ℃, after the reaction is finished, adding 300ml of 9mol/L HCl solution, heating to reflux, cooling to room temperature after the reflux reaction is finished, concentrating under reduced pressure, adding 500ml of ethanol into the concentrated solution, crystallizing, filtering, and drying by blowing at 40 ℃ under normal pressure to obtain a white zoledronic acid crude product; adding 2000ml of purified water into the obtained zoledronic acid crude product, heating to reflux, adding 0.5g of activated carbon for decoloring for 30min after complete dissolution, carrying out suction filtration while hot, cooling the filtrate to room temperature under stirring, crystallizing, carrying out suction filtration, and carrying out forced air drying at 40 ℃ under normal pressure to obtain 95.42g of zoledronic acid, wherein the yield is 91.78%.

The total yield is 77.93%, the purity is 99.82%, and the impurity content of the diphosphate is 0%.

Comparative example 1

In a 500ml three-necked flask, 15g of imidazole and 200ml of 1, 4-dioxane were added and dissolved by stirring at room temperature. Adding 10g of sodium hydroxide and 7.5g of benzyl triethyl ammonium chloride, uniformly stirring, dropwise adding about 40ml of excessive ethyl chloroacetate, and completely reacting after 0.5 h. At room temperature, 36g of phosphorous acid is added and stirred to be dissolved, then 38ml of excessive phosphorus trichloride is slowly dripped, after 1 hour, the dripping is finished, the reaction is complete, and the mixture is kept stand at room temperature overnight. Starting a machine to stir, slowly dripping 70ml of distilled water, dripping 70ml of concentrated hydrochloric acid, uniformly stirring, reacting for 6 hours, filtering reaction liquid after complete reaction, discarding filter residue, carrying out reduced pressure spin-drying on filtrate at 60 ℃, slowly dripping 200ml of methanol under the stirring condition, slowly getting turbid solution, and filtering to obtain flocculent viscous substance. Dissolving the viscous substance in 50ml distilled water, filtering to remove impurities, adding methanol dropwise, refrigerating for crystallization after about 50ml, and vacuum drying at 50 deg.C to obtain total 36.3g zoledronic acid.

The total yield is 60.5%, the purity is 97.54%, and the impurity of the diphosphate is 0.49%.

Comparative example 2

500ml of 1, 4-dioxane and 40g of 60% sodium hydride are added to the reaction solution, and 150ml of 1, 4-dioxane solution of 68g of imidazole is added dropwise with stirring in an ice water bath. The mixture was stirred at room temperature for 30 minutes, 122.5g of ethyl chloroacetate was added dropwise, and the mixture was stirred at room temperature for reaction for 3 hours. Slowly adding 200ml of 85 percent phosphoric acid, heating to 50-60 ℃ for reaction for 4 hours, dropwise adding 200ml of phosphorus trichloride at the temperature, and controlling the dropwise adding speed to finish the dropwise adding within about 1 hour. Heating to reflux reaction for 4 hours, cooling to 50-60 ℃, adding 500ml of 6mol/L hydrochloric acid, and heating to reflux reaction for 3 hours. Cooling, crystallizing while stirring, filtering, collecting precipitated solid, washing with a small amount of ethanol, and recrystallizing in distilled water to obtain 93.9g of zoledronic acid.

The total yield is 34.54%, the purity is 84.66%, and the impurity of the diphosphate is 0.14%.