A preparation method of zoledronic acid impurity B

Abstract

The invention discloses a method for preparing zoledronic acid impurity B, comprising the following steps: ① preparing intermediate I by nucleophilic substitution of imidazole and halogenated acetic acid ester, ② hydrolyzing and purifying intermediate I to prepare intermediate II; ③ preparing zoledronic acid impurity B; adding intermediate II, phosphoric acid or phosphorous acid, and solvent into a reaction container, stirring and heating to 35±5°C; dropping phosphorus trichloride into the reaction container, heating to 65±5°C and reacting for 3-5h after the addition; cooling to room temperature after the reaction of this part, dropping water into the material, heating to 95±5°C and reacting for 2-3h after the addition, and the reaction ends; cooling the reaction system and purifying to obtain zoledronic acid impurity B. The invention improves the reaction route and process of zoledronic acid impurity B, screens a series of influencing factors such as reaction raw materials, solvent type, reaction temperature, equivalent number, system concentration, etc., and the obtained product has a purity of>98%, which can be used as a reference substance.

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry, and particularly relates to a method for preparing zoledronic acid impurity B. Background Art

[0002] Zoledronic acid is a third-generation heterocyclic bisphosphonate for the treatment of hypercalcemia. Its chemical name is 1-hydroxy-2-(1-imidazolyl)ethylene-1,1-diphosphonic acid. Compared with the first-generation bisphosphonates (clomphosphonate, etidronate) and the second-generation bisphosphonates (tiludronate, aminopropyl bisphosphonate), zoledronic acid has better potency, longer duration of action and smaller dosage. As a bisphosphonate compound that specifically acts on bones, zoledronic acid can inhibit bone resorption caused by increased osteoclast activity, but has no adverse effects on bone formation, mineralization and mechanical properties. It is mainly used to treat hypercalcemia caused by tumors (TIH or HCM), inhibit bone metastasis caused by tumors and osteoporosis in menopausal women.

[0003] Zoledronic acid produces a lot of impurities during the synthesis process. In order to ensure the safety and effectiveness of the drug, it is very necessary to study and control the impurities during the synthesis process. The original Novartis patent document US4939130 discloses a method for synthesizing zoledronic acid. The synthetic route is shown in Figure 1 Among them, impurity A and impurity B are key impurities in zoledronic acid raw materials, and it is necessary to reasonably control their limits.

[0004] With the advancement of the country's work on drug consistency, determining the preparation methods of various impurity compounds and providing qualified reference materials can play a more active role in the quality control of zoledronic acid raw materials.

[0005] However, there are few reports on ideal synthesis methods of specific impurity B of zoledronic acid. Therefore, the present application is devoted to studying a synthesis method of impurity B to prepare zoledronic acid impurity B with higher purity for comparison with impurities in the actual production process, so as to control impurities in the existing production process. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide an exclusive synthesis method for impurity B of zoledronic acid. The obtained product has high purity and can be directly used as a synthetic reference substance of zoledronic acid.

[0007] The technical solution for achieving the purpose of the present invention is a method for preparing zoledronic acid impurity B, comprising the following steps:

[0008] ① Prepare intermediate Ⅰ by nucleophilic substitution of imidazole and halogenated acetate, wherein R is C1-C3-alkyl, t-Bu, benzyl, substituted benzyl or aromatic group.

[0009]

[0010] ②Hydrolyze and purify intermediate I to prepare intermediate II.

[0011]

[0012] ③Preparation of zoledronic acid impurity B.

[0013] Add intermediate II, phosphoric acid or phosphorous acid, and solvent to a reaction vessel, stir and heat to 35±5°C; add phosphorus trichloride dropwise to the reaction vessel, heat to 65±5°C and react for 3-5h after addition; cool to room temperature after the reaction, add water dropwise to the material, heat to 95±5°C and react for 2-3h after addition, and the reaction ends; cool the reaction system and purify to obtain zoledronic acid impurity B. The molar ratio of intermediate II to phosphoric acid or phosphorous acid is 1:4-6, and the molar ratio of intermediate II to phosphoric acid trichloride is 1:3-5.

[0014] In the above step ①, after dissolving imidazole, add metal iodide and base, and stir at 0℃~40℃ for 1~3 hours; then add halogenated acetate to the reaction system, stir and react at 0℃~40℃ for 20~40 hours, filter the obtained reaction solution and concentrate the filtrate. The metal iodide is sodium iodide and / or potassium iodide, and the amount of metal iodide is 0.01~0.1 times the amount of imidazole. The base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the amount of base is 1.5~3.0 times the amount of imidazole. The halogenated acetate is selected from methyl chloroacetate, methyl bromoacetate, ethyl chloroacetate, ethyl bromoacetate, tert-butyl chloroacetate, tert-butyl bromoacetate, phenyl chloroacetate, phenyl bromoacetate, benzyl chloroacetate, benzyl bromoacetate, etc.

[0015] In the above step ③, the solvent is one or a mixed solvent of more than one of sulfolane, chlorobenzene, diethylene glycol dimethyl ether, dioxane, and tetrahydrofuran.

[0016] In the above step ③, the molar ratio of intermediate II to phosphoric acid or phosphorous acid is 1:4-5.

[0017] In the above step ③, the molar ratio of intermediate II to phosphorus trichloride is 1:3-4.

[0018] In the above step ③, the reaction system is cooled to below 60° C., and then the reacted material is added dropwise to methanol and stirred for dispersion, and filtered to obtain a crude product; the crude product is added to a water / methanol solution for slurry purification, and then filtered and dried to obtain zoledronic acid impurity B.

[0019] The present invention has positive effects: the present invention improves the reaction route and process of zoledronic acid impurity B, screens a series of influencing factors such as reaction raw materials, solvent type, reaction temperature, equivalent number, system concentration, etc., and the obtained product has a purity of >98% and can be used as a reference product. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The synthetic route of zoledronic acid.

[0021] Figure 2 The synthetic route of zoledronic acid impurity B in this application is shown in FIG.

[0022] Figure 3 This is the HPLC chart of zoledronic acid impurity B prepared in Example 1.

[0023] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of the compound prepared in Example 1.

[0024] Figure 5 This is the mass spectrum of the compound prepared in Example 1. DETAILED DESCRIPTION

[0025] What are described below are some of the multiple possible embodiments of the preparation method of zoledronic acid impurity B of the present invention, which are intended to provide a basic understanding of the present invention, and are not intended to confirm the key or decisive elements of the present invention or to limit the scope to be protected. It is easy to understand that according to the technical solution of the present invention, without changing the essential spirit of the present invention, a person of ordinary skill in the art can propose other mutually replaceable implementations. Therefore, the following specific embodiments are only exemplary illustrations of the technical solution of the present invention, and should not be regarded as all of the present invention or as a limitation or restriction to the technical solution of the present invention.

[0026] (Example 1)

[0027] The preparation route of zoledronic acid impurity B in this example is shown in Figure 2 Specifically, the preparation method of zoledronic acid impurity B in this embodiment comprises the following steps:

[0028] ① Preparation of intermediate I. Add 20.0g (0.29mol) imidazole and 160mL dichloromethane to a 500mL four-necked bottle, stir and dissolve; add 60.9g (0.44mol) potassium carbonate and 2.2g (0.015mol) sodium iodide to the bottle, stir at 20℃~30℃ for 1±0.5 hours; then add 63.8g (0.59mol) methyl chloroacetate to the bottle, stir and react at 20℃~40℃ for 24±0.5 hours, stop the reaction to obtain a reaction solution. Filter the reaction solution, and concentrate the filtrate to 20%~40% of the original volume (25% in this embodiment) by reduced pressure rotary evaporation to obtain a concentrated solution of intermediate I.

[0029] The solvent for dissolving imidazole is one of tetrahydrofuran, 1,4-dioxane, and dichloromethane or a mixture of more than one of them. In this embodiment, dichloromethane is used.

[0030] In addition to sodium iodide, the metal iodide may also be potassium iodide, or sodium iodide + potassium iodide. The amount of the metal iodide is 0.03 to 0.05 times the amount of the imidazole.

[0031] The base specifically used in this embodiment is potassium carbonate. Optionally, the base is one or a mixture of more than one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. The amount of the base is 1.5 to 3.0 times the amount of the imidazole.

[0032] In the general formula of intermediate I, R is C1-C3-alkyl, t -Bu, benzyl, substituted benzyl or aromatic group, methyl in this embodiment. In addition to the methyl chloroacetate used in this embodiment, other halogenated acetates with corresponding substituents can also be selected, such as methyl bromoacetate, ethyl chloroacetate, ethyl bromoacetate, tert-butyl chloroacetate, tert-butyl bromoacetate, etc. The amount of the halogenated acetate is 2.0 to 3.0 times the amount of the imidazole.

[0033] ② Preparation of intermediate II. Add 50 mL of water to the concentrated solution of intermediate I obtained in step ①, and stir the reaction at 70°C to 80°C for 10±0.5 hours; after the reaction, pour the reaction solution into 300 mL of a dispersing solvent, disperse it, and filter it to obtain a crude intermediate (II).

[0034] The crude intermediate II obtained above was added into 100 mL of an organic / inorganic mixed solvent (tetrahydrofuran: water = 4:1) and purified by slurrying to obtain 39.5 g (0.21 mol) of intermediate II with a molar yield of 73.9% and a purity of 98.4% as determined by HPLC.

[0035] The confirmation data of Intermediate II are as follows:

[0036] 1 H NMR (600MHz, D2O) δ: 8.71(s, 1H), 7.37(d, 2H), 4.87(s, 4H).

[0037] 13 C NMR (600MHz, DO) δ: 170.90, 137.78, 123.38, 51.02.

[0038] IR(KBr)cm -1: 3145.10, 2959.91, 1664.05, 1562.85, 1333.33, 1168.09,874.03, 749.91, 675.94, 424.51.

[0039] In this step, the dispersion solvent is one or a mixture of more than one of methanol, ethanol, isopropanol, tetrahydrofuran, ether, and acetone. The dispersion solvent in this embodiment is ethanol.

[0040] Optionally, in the organic / inorganic mixed solvent, the organic solvent is ethanol and / or tetrahydrofuran, the inorganic solvent is water, and the volume ratio of the organic / inorganic solvent is 3 to 5:1.

[0041] ③Prepare impurity B.

[0042] 2 g (0.011 mol) of intermediate II, 4.5 g (0.055 mol) of phosphorous acid and 10 mL of solvent sulfolane were added to a 50 mL single-necked bottle, and the mixture was heated to 35±5° C. (35° C. in this embodiment) with stirring and stirred for 1 hour.

[0043] The solvent may be any solvent that has no adverse effect on the reaction, preferably one or a mixed solvent of sulfolane, chlorobenzene, diethylene glycol dimethyl ether, dioxane, and tetrahydrofuran.

[0044] 4.5 g (0.033 mol) of phosphorus trichloride was added dropwise to the bottle. After the addition, the temperature was raised to 65±5° C. (65° C. in this embodiment) and the reaction was continued for 3 to 5 hours (4 hours in this embodiment).

[0045] After the reaction is completed, the mixture is cooled to room temperature, 16 mL of water is added dropwise to the material, and the temperature is raised to 95±5° C. (95° C. in this embodiment) and reacted for 2 to 3 h (2 hours in this embodiment), and the reaction is completed.

[0046] The reaction system was cooled to below 60° C., and the reacted material was then added dropwise into 30 mL of methanol and stirred for 1 to 2 h, and the crude product was obtained by filtration.

[0047] The crude product was added to 20 mL of 20% water / methanol solution and purified by slurrying for 1-2 h, then filtered and dried to obtain 3.1 g (0.0065 mol) of impurity B with a molar yield of 59.1%. The purity was 98.83% as determined by HPLC. The HPLC spectrum is shown in Figure 3 .

[0048] The compound prepared in this step was confirmed, and the H NMR spectrum was shown in Figure 4 , mass spectrum see Figure 5 , the specific test results are as follows:

[0049] 1H NMR (600MHz, D2O) δ: 8.76(s, 1H), 7.41(d, 2H), 4.63(m, 4H).

[0050] MS (ESI, m / z): 476.1 (MH + ).

[0051] It was confirmed that the compound prepared in this example was zoledronic acid impurity B.

[0052] (Example 2)

[0053] The preparation method of zoledronic acid impurity B in this example is the same as that in Example 1 except that:

[0054] In step ③, 0.01 mol of intermediate II, 0.05 mol of phosphoric acid and 10 mL of tetrahydrofuran solvent were added to a 50 mL single-necked bottle, and the mixture was heated to 30° C. with stirring and stirred at the same temperature for 1 hour.

[0055] (Example 3)

[0056] The preparation method of zoledronic acid impurity B in this example is the same as that in Example 1 except that:

[0057] In step ③, the molar ratio of intermediate II to phosphorous acid is 1:4; the molar ratio of intermediate II to phosphorus trichloride is 1:4.

[0058] (Example 4)

[0059] The preparation method of zoledronic acid impurity B in this example is the same as that in Example 1 except that:

[0060] In step ③, the molar ratio of intermediate II to phosphorous acid is 1:6; the molar ratio of intermediate II to phosphorus trichloride is 1:5.

[0061] Step ③ is carried out under acidic conditions. In order to improve the reaction efficiency of the starting intermediate II, an excess of phosphorous acid (or phosphoric acid) is used, for example, 4 to 6 times the molar amount relative to the starting material, preferably 4 to 5.5 times the molar amount; at the same time, an excess of phosphorus trichloride (3 to 5 times the molar amount relative to the starting material, preferably 3 to 4 times the molar amount) is used to selectively react to obtain the zoledronic acid impurity B.

Claims

1. A method for preparing zoledronic acid impurity B, characterized in that The following steps are involved: ① Prepare intermediate Ⅰ by nucleophilic substitution of imidazole and halogenated acetate, wherein R is C1-C3-alkyl or t -Bu; After dissolving imidazole, add metal iodide and base, and stir at 0°C to 40°C for 1 to 3 hours; then add halogenated acetate to the reaction system, stir at 0°C to 40°C for 20 to 40 hours, filter the obtained reaction solution, and concentrate the filtrate; The solvent for dissolving imidazole is one or a mixture of more than one of tetrahydrofuran, 1,4-dioxane and dichloromethane; ② Hydrolyze and purify intermediate I to prepare intermediate II; ③ Preparation of zoledronic acid impurity B; Add intermediate II, phosphoric acid or phosphorous acid, and solvent into a reaction vessel, stir and heat to 35±5°C; drop phosphorus trichloride into the reaction vessel, heat to 65±5°C and react for 3-5h after addition; cool to room temperature after reaction, drop water into the material, heat to 95±5°C and react for 2-3h after addition, and the reaction is finished; cool the reaction system and purify to obtain zoledronic acid impurity B; The molar ratio of the intermediate II to phosphoric acid or phosphorous acid is 1:4-6, and the molar ratio of the intermediate II to phosphorus trichloride is 1:3-5.

2. The method for preparing zoledronic acid impurity B according to claim 1, characterized in that: In step ③, the solvent is one or a mixed solvent of more than one of sulfolane, chlorobenzene, diethylene glycol dimethyl ether, dioxane, and tetrahydrofuran.

3. The method for preparing zoledronic acid impurity B according to claim 1, characterized in that: In step ③, the molar ratio of intermediate II to phosphoric acid or phosphorous acid is 1:4-5.

4. The method for preparing zoledronic acid impurity B according to claim 1, characterized in that: In step ③, the molar ratio of intermediate II to phosphorus trichloride is 1:3-4.

5. The method for preparing zoledronic acid impurity B according to claim 1, characterized in that: In step ③, the reaction system is cooled to below 60° C., and then the reacted material is added dropwise to methanol and stirred for dispersion, and filtered to obtain a crude product; the crude product is added to a water / methanol solution for slurry purification, and then filtered and dried to obtain zoledronic acid impurity B.

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