A kind of preparation method of zoledronic acid

Abstract

The invention discloses a method for preparing zoledronic acid, comprising reacting imidazoleacetic acid, phosphoric acid or phosphorous acid, phosphorus trichloride or phosphorus oxychloride in an inert solvent under the catalysis of a solid acid catalyst at 40°C to 80°C for 2 to 5 hours, adding water and hydrolyzing at 80°C to 120°C for 1 to 5 hours, filtering by suction, and adding an organic solvent to the filtrate for crystallization to obtain zoledronic acid monohydrate. The invention uses imidazoleacetic acid as a starting material, utilizes a solid acid catalyst to promote the progress of the reaction, solves the problem of solidification of the reaction system, and greatly improves the yield of zoledronic acid monohydrate, the yield of zoledronic acid monohydrate reaches more than 85%; at the same time, the obtained zoledronic acid monohydrate has high purity and good properties.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing zoledronic acid. Background Art

[0002] Zoledronic acid, chemically named [1-hydroxy-2-(1-imidazolyl)ethylidene] diphosphonic acid monohydrate, is a third-generation heterocyclic bisphosphonic acid drug for the treatment of hypercalcemia. Zoledronic acid is a diphosphonic acid compound that specifically acts on bones. It can inhibit bone resorption caused by increased osteoclast activity, but has no adverse effects on bone formation, bone mineralization and mechanical properties. It is mainly used to treat hypercalcemia caused by tumors (TIH or HCM), to inhibit bone metastasis caused by tumors, and osteoporosis in menopausal women.

[0003] As a new anti-tumor drug, zoledronic acid has better therapeutic effects and lower dosage than previous generations of osteoporosis drugs. Clinical trials have shown that it is the most effective bisphosphonate compound to date, which makes the market prospect of zoledronic acid very good. Compared with the large market demand, the synthesis yield of zoledronic acid is low, so the price of the drug has remained high.

[0004] The main bottleneck in the manufacture of bisphosphonates is the solidification of the reaction system involved.

[0005] Chinese patent document CN 101443341A (application number 200780017315.5) discloses a method for manufacturing bisphosphonic acid, in which dimethyl glycol ether, dimethyl glycol ether or a mixture thereof is used to generate a uniform solid that can be easily dispersed in water, attempting to solve the problem of gradual thickening of the two-phase system, but the final yield is only about 28%, which is not ideal. The step-by-step synthesis of zoledronic acid disclosed in Chinese patent document CN 1472215A and the one-step synthesis of zoledronic acid disclosed in Chinese patent document CN1693308A also encounter similar problems, which ultimately result in the low yield of the product zoledronic acid, which is about 20% to 30%. How to solve this difficult problem of synthesizing bisphosphonic acid drugs, thereby thoroughly improving the yield of zoledronic acid, is the focus of the present invention.

[0006] U.S. Patent No. 4,939,130 ​​and Patent W02005063717 disclose a method for synthesizing zoledronic acid, which comprises using imidazole-1-acetic acid hydrochloride as a starting material and reacting phosphorus trichloride or phosphorus oxychloride with phosphorous acid or phosphoric acid in the presence of a large amount of chlorobenzene, followed by hydrolysis to synthesize zoledronic acid. This method uses chlorobenzene as a solvent, which is extremely harmful to the human body and the environment, and has the problem of difficulty in stirring.

[0007] Patent W03093282 uses an ionizing agent as a solvent, which solves the problem of difficult stirring, but has the disadvantage of low yield, and the post-treatment repeatedly adjusts the acid and alkali, and methanol is added to the aqueous phase to precipitate the product, which is easy to form an oily substance. Similarly, Chinese patent CN104610357A uses imidazole-1-acetic acid hydrochloride as a raw material and an ionizing agent as a solvent. In the post-treatment process, hydrochloric acid is first added for hydrolysis, filtration, and the filter cake is then added with hydrochloric acid for hydrolysis. After hydrolysis, the filtrate is combined and distilled to dryness under reduced pressure, and then an organic solvent is added for stirring and crystallization. The post-treatment process is relatively complicated, involving evaporation of a large amount of hydrochloric acid aqueous solution, and after evaporation, the oily substance is directly added with an organic solvent. At the same time, the zoledronic acid product prepared by the above solvent method has poor purity and high impurity content.

[0008] Chinese patent document CN 102070668B (application number 201010610896.7) discloses a method for preparing zoledronic acid and its sodium salt using a phase transfer catalyst, wherein imidazole and α-haloacetic acid ester react in a solvent under alkaline conditions in a phase transfer catalyst, then react with phosphorous acid and phosphorus trichloride, then add water to remove excess phosphorus trichloride, and hydrolyze under acidic conditions to obtain zoledronic acid; the phase transfer catalyst is benzyltriethylammonium chloride. The invention uses a phase transfer catalyst to promote the progress of the reaction and has a high reaction yield. The specification states that the total yield of the synthesis can be increased to about 60%. Summary of the invention

[0009] The technical problem to be solved by the present invention is to provide a method for preparing zoledronic acid with high purity and high yield.

[0010] The technical solution for achieving the purpose of the present invention is a method for preparing zoledronic acid. The method comprises the following steps: reacting imidazoleacetic acid, phosphoric acid or phosphorous acid, phosphorus trichloride or phosphorus oxychloride in an inert solvent at 40°C to 80°C for 2 to 5 hours under the catalysis of a solid acid catalyst, adding water, hydrolyzing at 80°C to 120°C for 1 to 5 hours, filtering with suction, and adding an organic solvent to the filtrate for crystallization to obtain zoledronic acid monohydrate.

[0011] Preferably, the molar ratio of phosphoric acid or phosphorous acid to imidazole acetic acid is 3.0 to 8.0:1.

[0012] Preferably, the molar ratio of phosphorus trichloride or phosphorus oxychloride to imidazole acetic acid is 3.0-5.0:1.

[0013] The inert solvent is sulfolane or diethylene glycol dimethyl ether, or a mixed solvent of sulfolane and diethylene glycol dimethyl ether.

[0014] Furthermore, corresponding to 1 g of the starting material imidazole acetic acid, the amount of the inert solvent used is 5 to 10 mL.

[0015] The solid acid catalyst is one of amberlyst15, amberlyst35, amberlyst36, amberlyst45, amberlyst21 and amberlyst26; and the amount of the solid acid catalyst is 3% to 10% of the mass of imidazole acetic acid.

[0016] Preferably, corresponding to 1 g of the starting material imidazole acetic acid, the amount of purified water used during hydrolysis is 5 to 15 mL.

[0017] The organic solvent used in crystallization is one or a mixed solvent of more than one of methanol, ethanol and isopropanol.

[0018] Preferably, the amount of the organic solvent used in the crystallization is 5-15 mL corresponding to 1 g of the starting material imidazole acetic acid.

[0019] During the synthesis process, imidazole acetic acid, phosphoric acid or phosphorous acid, an inert solvent and a solid acid catalyst are first added to a reaction bottle, and after the temperature is raised to 40°C to 80°C, phosphorus trichloride or phosphorus oxychloride is added dropwise, and the reaction is carried out at 40°C to 80°C.

[0020] The present invention has positive effects:

[0021] (1) The present invention uses imidazoleacetic acid as a starting material and utilizes a solid acid catalyst to promote the progress of the reaction, thereby solving the problem of solidification of the reaction system and greatly improving the yield of zoledronic acid monohydrate. The yield of zoledronic acid monohydrate reaches more than 85%; at the same time, the obtained zoledronic acid monohydrate has high purity and good properties.

[0022] (2) The solid acid catalyst used in the present invention can be recycled and is suitable for continuous equipment; it is non-corrosive and does not cause any damage to the equipment; the product is easy to separate, and after the reaction is completed, the product and the catalyst can be separated by filtering; there is no wastewater discharge and no need for neutralization and water washing; it has good low-temperature activity, strong selectivity, and few side reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the HPLC spectrum of the compound prepared in Example 1.

[0024] Figure 2 This is the infrared spectrum of the compound prepared in Example 1.

[0025] Figure 3 This is the H NMR spectrum of the compound prepared in Example 1.

[0026] Figure 4 This is the C NMR spectrum of the compound prepared in Example 1.

[0027] Figure 5 This is a high-resolution mass spectrum of the compound prepared in Example 1.

[0028] Figure 6 This is the TGA detection chart of the compound prepared in Example 1. DETAILED DESCRIPTION

[0029] The reaction equation for preparing zoledronic acid of the present invention is as follows:

[0030] .

[0031] The preparation method is as follows: imidazole acetic acid, phosphoric acid or phosphorous acid and phosphorus trichloride or phosphorus oxychloride are reacted in an inert solvent.

[0032] Under the catalysis of a solid acid catalyst, react at 40°C to 80°C for 2 to 5 hours, add water and hydrolyze at 80°C to 120°C for 1 to 5 hours, filter with suction, and add an organic solvent to the filtrate for crystallization to obtain zoledronic acid monohydrate.

[0033] Wherein, the molar ratio of phosphoric acid or phosphorous acid to imidazole acetic acid is 3.0-8.0:1; the molar ratio of phosphorus trichloride or phosphorus oxychloride to imidazole acetic acid is 3.0-5.0:1.

[0034] The inert solvent is cyclopentane sulfone and / or diethylene glycol dimethyl ether, and the volume mass ratio of the inert solvent to imidazole acetic acid is 5-10 (mL):1 (g), that is, corresponding to 1g of the starting material imidazole acetic acid, the amount of the inert solvent is 5-10mL.

[0035] The solid acid catalyst is one of amberlyst15, amberlyst35, amberlyst36, amberlyst45, amberlyst21 and amberlyst26; and the amount of the solid acid catalyst is 3% to 10% of the mass of the imidazole acetic acid.

[0036] The volume mass ratio of purified water to the starting material imidazole acetic acid used in the hydrolysis is 5-15 (mL):1 (g); that is, corresponding to 1g of the starting material imidazole acetic acid, the amount of purified water used is 5-15mL.

[0037] The organic solvent used in crystallization is one or more of methanol, ethanol, and isopropanol, and the volume mass ratio of the organic solvent to the starting material imidazole acetic acid is 5-15 (mL): 1 (g); that is, corresponding to 1g of the starting material imidazole acetic acid, the amount of the organic solvent used in crystallization is 5-15mL.

[0038] (Example 1)

[0039] The preparation method of zoledronic acid of the present embodiment is as follows:

[0040] Add 20 g of imidazoleacetic acid, 100 mL of cyclopentane, 65 g of solid phosphorous acid and 1 g of Amberlyst-15 solid acid catalyst to the reaction flask, and heat to 60°C; add 65 g of phosphorus trichloride dropwise, and continue to react at 60°C for 3 hours after the addition is completed; add 200 mL of purified water dropwise to the reaction flask, and reflux at 100°C for 2 hours.

[0041] After the hydrolysis reaction was completed, the mixture was filtered while hot, 200 mL of ethanol was added to the filtrate and stirred for crystallization for 1 hour, and then filtered with suction. The filter cake was dried to obtain 42.5 g of zoledronic acid monohydrate with a yield of 92.4%. The product was sent for HPLC analysis ( Figure 1 ), purity 100%, sent for infrared testing ( Figure 2 )、NMR( Figure 3 Hydrogen spectrum, Figure 4 Carbon spectrum), high resolution mass spectrometry ( Figure 5 )、TGA test( Figure 6 ) for structural identification and the analytical results were correct.

[0042] The infrared spectrum analysis is as follows:

[0043]

[0044] The hydrogen spectrum analysis is as follows:

[0045]

[0046]

[0047] The carbon spectrum analysis is as follows:

[0048]

[0049]

[0050] The high-resolution mass spectrometry analysis is as follows:

[0051] The measured molecular weight of HRMS analysis was 270.99 (M-1), which was consistent with the theoretical molecular weight 270.99 (M-1), and the corresponding molecular formula was consistent with that of zoledronic acid.

[0052] TGA analysis is as follows:

[0053] The sample loses 6.2% of its weight at about 160-170°C. This weight loss is caused by the disappearance of crystal water. Calculation shows that it is a monohydrate (18÷290.1=6.2%).

[0054] (Example 2)

[0055] The preparation method of zoledronic acid in this embodiment is as follows: 20 g of imidazoleacetic acid, 120 mL of diethylene glycol dimethyl ether, 78 g of solid phosphorous acid and 2 g of Amberlyst-35 solid acid catalyst are added to a reaction flask, the temperature is raised to 55 ° C, 78 g of phosphorus trichloride is added dropwise, and the reaction is continued at 55 ° C for 2.5 hours after the addition is completed; 240 mL of purified water is added dropwise to the reaction flask, and refluxed at 110 ° C for 1.5 hours.

[0056] The mixture was filtered while hot, 240 mL of methanol was added to the filtrate and stirred for crystallization for 1 hour, and then filtered with suction. The filter cake was dried to obtain 41.3 g of zoledronic acid monohydrate with a yield of 89.78%.

[0057] (Example 3)

[0058] The preparation method of zoledronic acid in this embodiment is as follows: 20 g of imidazoleacetic acid, 60 mL of cyclopentane, 60 mL of diethylene glycol dimethyl ether, 93.2 g of phosphoric acid and 1 g of Amberlyst-21 solid acid catalyst were added to a reaction flask, the temperature was raised to 65 ° C, 72.6 g of phosphorus oxychloride was added dropwise, and the reaction was continued at 70 ° C for 3.5 hours after the addition was completed; 220 mL of purified water was added dropwise to the reaction flask, and refluxed at 115 ° C for 2.5 hours.

[0059] The mixture was filtered while hot, 220 mL of isopropanol was added to the filtrate, and the mixture was stirred for crystallization for 1 hour. The mixture was filtered with suction, and the filter cake was dried to obtain 40.8 g of zoledronic acid monohydrate with a yield of 88.69%.

[0060] (Example 4)

[0061] Add 20 g of imidazoleacetic acid, 80 mL of sulfolane, 80 mL of diethylene glycol dimethyl ether, 93.2 g of phosphoric acid and 0.6 g of Amberlyst-26 solid acid catalyst to the reaction flask, raise the temperature to 70°C, add 72.6 g of phosphorus oxychloride dropwise, and continue to react at 65°C for 4 hours after the addition is completed; add 260 mL of purified water dropwise to the reaction flask, and reflux at 120°C for 1 hour.

[0062] The mixture was filtered while hot, 260 mL of methanol was added to the filtrate and stirred for crystallization for 1 hour, and then filtered with suction. The filter cake was dried to obtain 39.5 g of zoledronic acid monohydrate with a yield of 85.87%.

[0063] (Example 5)

[0064] Add 20 g of imidazoleacetic acid, 80 mL of cyclopentane sulfone, 80 mL of diethylene glycol dimethyl ether, 65 g of solid phosphorous acid and 1 g of Amberlyst-36 solid acid catalyst to the reaction flask, raise the temperature to 75°C, add 65 g of phosphorus trichloride dropwise, continue the reaction at 75°C for 3 hours, add 160 mL of purified water dropwise to the reaction flask, and reflux at 105°C for 2.5 hours.

[0065] The mixture was filtered while hot, 160 mL of isopropanol was added to the filtrate, stirred and crystallized for 1 hour, filtered with suction, and the filter cake was dried to obtain 40.5 g of zoledronic acid monohydrate with a yield of 88.04%.

[0066] (Example 6)

[0067] Add 20 g of imidazoleacetic acid, 90 mL of sulfolane, 90 mL of diethylene glycol dimethyl ether, 77.7 g of phosphoric acid and 1.5 g of Amberlyst-45 solid acid catalyst to the reaction flask, raise the temperature to 60°C, add 65 g of phosphorus trichloride dropwise, continue the reaction at 60°C for 3 hours, add 200 mL of purified water dropwise to the reaction flask, and reflux at 100°C for 3 hours.

[0068] The mixture was filtered while hot, 200 mL of ethanol was added to the filtrate and stirred for crystallization for 1 hour, and the mixture was filtered with suction. The filter cake was dried to obtain 41.8 g of zoledronic acid monohydrate with a yield of 90.87%.

Claims

1. A method for preparing zoledronic acid, characterized in that: Imidazoleacetic acid, phosphoric acid or phosphorous acid, phosphorus trichloride or phosphorus oxychloride are reacted in an inert solvent at 40°C to 80°C for 2 to 5 hours under the catalysis of a solid acid catalyst, and then water is added and hydrolyzed at 80°C to 120°C for 1 to 5 hours, and filtered with suction, and the filtrate is added with an organic solvent for crystallization to obtain zoledronic acid monohydrate; the reaction formula is as follows: ； The solid acid catalyst is one of amberlyst15, amberlyst35, amberlyst36, amberlyst45, amberlyst21 and amberlyst26, and the amount of the solid acid catalyst is 3% to 10% of the mass of the imidazole acetic acid.

2. The method for preparing zoledronic acid according to claim 1, characterized in that: The molar ratio of phosphoric acid or phosphorous acid to imidazole acetic acid is 3.0 to 8.0:

1.

3. The method for preparing zoledronic acid according to claim 1, characterized in that: The molar ratio of phosphorus trichloride or phosphorus oxychloride to imidazole acetic acid is 3.0-5.0:

1.

4. The method for preparing zoledronic acid according to claim 1, characterized in that: The inert solvent is sulfolane or diethylene glycol dimethyl ether, or a mixed solvent of sulfolane and diethylene glycol dimethyl ether.

5. The method for preparing zoledronic acid according to claim 4, characterized in that: Corresponding to 1g of the starting material imidazole acetic acid, the amount of inert solvent used is 5-10mL.

6. The method for preparing zoledronic acid according to claim 1, characterized in that: Corresponding to 1g of the starting material imidazole acetic acid, the amount of purified water used during hydrolysis is 5-15mL.

7. The method for preparing zoledronic acid according to claim 1, characterized in that: The organic solvent used in crystallization is one or a mixed solvent of more than one of methanol, ethanol and isopropanol.

8. The method for preparing zoledronic acid according to claim 7, characterized in that: Corresponding to 1g of the starting material imidazole acetic acid, the amount of organic solvent used in crystallization is 5-15mL.

9. The method for preparing zoledronic acid according to any one of claims 1 to 8, characterized in that: First add imidazoleacetic acid, phosphoric acid or phosphorous acid, an inert solvent and a solid acid catalyst into a reaction bottle, heat it to 40°C to 80°C, then drop phosphorus trichloride or phosphorus oxychloride and react at 40°C to 80°C.

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