Preparation method of zoledronic acid dimer

Abstract

The invention belongs to the technical field of medicine synthesis, and discloses a preparation method of zoledronic acid dimer impurities. The preparation method is novel, simple to operate, high in product purity and suitable for industrial production; the zoledronic acid dimer impurity synthesized by the invention can be used as a standard substance for detecting zoledronic acid raw material medicines and preparations, so that the accuracy of impurity content detection and analysis is improved, the impurity in the zoledronic acid raw material medicines and preparations is favorably controlled, and the quality of zoledronic acid finished products is further improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis and relates to a preparation method of zoledronic acid dimer. Background Art

[0002] Zoledronic acid, chemically named [1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]diphosphonic acid, is a third-generation bisphosphonate drug developed by Novartis AG of Switzerland. It was first marketed in Canada in October 2000 under the trade name This drug inhibits the abnormal activity of osteoclasts, inhibits the bone resorption of osteoclasts, reduces bone turnover, and thus normalizes the blood calcium concentration. Clinically, it is mainly used for the treatment of hypercalcemia (HCM) and osteoporosis caused by malignant tumors. The results of pharmacological experiments show that its effects of inhibiting bone metastasis and anti-bone resorption are 100-850 times those of the previous generations of bisphosphonates, and it is currently the bisphosphonate drug with the strongest pharmacological activity. The commonly used one in clinical practice is its monohydrate, and the structural formula is shown as follows:

[0003]

[0004] The main current synthetic route of zoledronic acid is as follows:

[0005]

[0006] In the zoledronic acid raw material drug synthesized by the above method, several process impurities such as zoledronic acid dimer are often produced, which affect the quality of the zoledronic acid raw material drug and its preparations. For pharmaceutical R & D personnel, the main work is not only how to obtain high-quality raw material drugs and develop efficient synthetic processes, but more importantly, to study the types and sources of impurities in the raw material drugs and how to control the generation of process impurities. Usually, researchers will first synthesize the impurities generated in the process directionally, and secondly, develop an efficient synthetic route for the impurities in order to obtain a large amount of impurity reference substances to ensure the development of the quality detection work for each batch of raw material drugs (such as impurity HPLC localization, impurity content determination, etc.). Therefore, it is very necessary to design and synthesize this impurity to provide a reference substance for the quality research of zoledronic acid.

[0007] There is currently no report in the literature on the synthesis of zoledronic acid dimer impurities. Therefore, it is of great significance to study and provide a preparation method for zoledronic acid dimer impurities. Summary of the Invention

[0008] Zoledronic acid dimer (the compound shown in Formula I) is a trace impurity existing in the preparation of zoledronic acid by the existing process. It is difficult to be effectively removed through post-treatment and refining processes, which affects the quality of zoledronic acid bulk drug. The content of this impurity in zoledronic acid is low, it is not easy to separate, and it is difficult to obtain in high purity and large quantities. In order to facilitate more in-depth research on the safety, stability and quality control in the production process of zoledronic acid-related medications, the present invention provides a synthesis method for zoledronic acid dimer impurity. This method is simple in operation, has high yield and purity, and is suitable for industrial production.

[0009]

[0010] The present invention is specifically realized through the following technical solutions:

[0011] A. Phosphorylate imidazole-1-acetic acid, and obtain the crude product of zoledronic acid dimer through further treatment;

[0012] B. Recrystallize the crude product to obtain the finished product of zoledronic acid dimer.

[0013] Preferably, the above synthesis scheme is further described in detail in the following parts:

[0014] Step A of the present invention is specifically carried out as follows: Dissolve imidazole-1-acetic acid in a sulfonic acid solvent, add a phosphorylating reagent to carry out a phosphorylation reaction, and hydrolyze the product obtained from the phosphorylation reaction. After the reaction is completed, adjust the pH with an alkali solution, keep warm for crystallization, filter and dry to obtain the crude product of zoledronic acid dimer.

[0015] Preferably, in step A, the sulfonic acid solvent is selected from one of C 1-6 alkyl sulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0016] Preferably, the C 1-6 alkyl sulfonic acid is selected from one of methyl sulfonic acid, ethyl sulfonic acid, propyl sulfonic acid and butyl sulfonic acid, and methanesulfonic acid is particularly preferred.

[0017] Preferably, in step A, the molar ratio of the feed of imidazole-1-acetic acid, sulfonic acid solvent, and phosphorylating reagent is 1:2-8:1-5, and 1:6:4 is particularly preferred.

[0018] Preferably, in step A, the phosphorylating reagent is selected from one of phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorous acid, and phosphoric acid, and phosphorous acid is particularly preferred.

[0019] Furthermore, in step A, the hydrolysis treatment includes:

[0020] (a) Cool the reaction solution after the phosphorylation reaction to room temperature;

[0021] (b) The volume molar ratio of the added purified water to imidazole-1-acetic acid is 1:0.3 to 0.6, preferably 1:0.4;

[0022] Furthermore, in step A, the pH adjustment with the alkaline solution includes:

[0023] (c) The base is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate, and sodium hydroxide is particularly preferred;

[0024] (d) The pH of the aqueous solution of the base is adjusted to 1.0 to 3.0; preferably, the pH is adjusted to 1.0 to 2.0.

[0025] Furthermore, in step A, the heat preservation and crystallization include:

[0026] (e) The heat preservation temperature is 10 to 50 °C;

[0027] (f) The heat preservation time is 0.5 to 5 h.

[0028] In the present invention, step B is specifically carried out as follows: The crude product of the compound shown in formula I is dissolved in water, heated, kept warm, then an alcohol solvent is added, followed by heat preservation and crystallization, filtration, and drying to obtain the finished product of zoledronic acid dimer.

[0029] The mass ratio of the compound of formula I to purified water is 1:1 to 1:6, and particularly preferably 1:2.

[0030] Furthermore, in step B, the heat preservation and stirring include:

[0031] (g) The heat preservation and stirring temperature is 60 to 90 °C; particularly preferably, the heat preservation temperature is 70 °C;

[0032] Furthermore, in step B, the alcohol solvent is selected from at least one of methanol, ethanol, and propanol.

[0033] Furthermore, in step B, the volume ratio of the purified water to the alcohol solvent is 1:1 to 3, and particularly preferably 1:2.

[0034] Furthermore, in step B, the heat preservation and crystallization include:

[0035] (h) The heat preservation and crystallization temperature is 5 to 40 °C, preferably 10 to 30 °C, and more preferably 20 °C;

[0036] (i) The heat preservation and crystallization time is 0.5 to 5 h.

[0037] In summary, the technical effects achieved by the present invention are:

[0038] 1. A method for preparing a zoledronic acid dimer impurity is provided. The synthetic method is simple to operate, has high yield and purity, mild reaction conditions, is economical and environmentally friendly, and is suitable for industrial production.

[0039] 2. There are no major impurities in the reaction of this synthetic route, which makes the reaction yield higher and the post-processing simpler. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 It is a zoledronic acid dimer impurity compound Ⅰ 1 H-NMR spectrum.

[0041] Figure 2 It is a zoledronic acid dimer impurity compound Ⅰ 13 C-NMR spectrum.

[0042] Figure 3 It is a zoledronic acid dimer impurity compound Ⅰ 31 P-NMR spectrum.

[0043] Figure 4 The HPLC spectrum of zoledronic acid dimer impurity compound I in zoledronic acid sample; the relative retention time of zoledronic acid dimer impurity is 8.129 minutes. DETAILED DESCRIPTION

[0044] The present invention is further described below by way of examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention, so simple improvements to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0045] All materials used in the experiments without indicating their sources and specifications were commercially available of analytical grade or chemically pure.

[0046] Example 1

[0047] Add methanesulfonic acid (390ml), phosphorous acid (4mol, 328g), and imidazole-1-acetic acid (1mol, 126.1g) to a 5L reaction bottle in sequence, stir until completely dissolved, and heat to 65°C for reaction. After the reaction is complete, the temperature is lowered to 20°C, 2.5L purified water is added, and the reaction is stirred for 0.5h. Then, 10mol / L sodium hydroxide solution is added to adjust the pH to 1-2, and solids are precipitated. Stirring and crystallization are continued for 3h. Centrifuge and discard the material, vacuum dry at 50°C for 6 hours to obtain a crude product of zoledronic acid dimer with a yield of 63.1%.

[0048] Add the crude product of zoledronic acid dimer and 1 L of purified water to a 5 L reaction flask in sequence, heat up to 70 °C, stir until completely dissolved, and continue to keep the temperature for 0.5 h. Cool the temperature to 30 °C, add 2 L of ethanol, and start crystallization. Cool the temperature to 20 °C and keep the temperature for crystallization for 3 h. Centrifuge to remove the mother liquor and dry in vacuum at 50 °C for 6 hours to obtain the finished product of zoledronic acid dimer, with a yield of 89.6% and an HPLC purity of 98.6%.

[0049] Example 2

[0050] Add benzenesulfonic acid (960 ml), phosphorus trichloride (5 mol, 686.5 g), and imidazole-1-acetic acid (1 mol, 126.1 g) to a 5 L reaction flask in sequence, stir until completely dissolved, and heat up to 65 °C for reaction. After detecting that the reaction is complete, cool the temperature to 30 °C, add 3 L of purified water, stir and react for 1 h, then add 10 mol / L sodium hydroxide solution to adjust the pH to 5 - 6, precipitate solids, and continue to stir and crystallize for 3 h. Centrifuge to remove the mother liquor and dry in vacuum at 50 °C for 6 hours to obtain the crude product of zoledronic acid dimer, with a yield of 58.6%.

[0051] Add the crude product of zoledronic acid dimer and 1 L of purified water to a 5 L reaction flask in sequence, heat up to 70 °C, stir until completely dissolved, and continue to keep the temperature for 0.5 h. Cool the temperature to 30 °C, add 3 L of methanol, and start crystallization. Cool the temperature to 30 °C and keep the temperature for crystallization for 3 h. Centrifuge to remove the mother liquor and dry in vacuum at 50 °C for 6 hours to obtain the finished product of zoledronic acid dimer, with a yield of 84.3% and an HPLC purity of 97.8%.

[0052] Example 3

[0053] Add p-toluenesulfonic acid (1610 ml), phosphorus pentachloride (7 mol, 1457.7 g), and imidazole-1-acetic acid (1 mol, 126.1 g) to a 5 L reaction flask in sequence, stir until completely dissolved, and heat up to 65 °C for reaction. After detecting that the reaction is complete, cool the temperature to 20 °C, add 3 L of purified water, stir and react for 0.5 h, then add 10 mol / L sodium hydroxide solution to adjust the pH to 3 - 4, precipitate solids, and continue to stir and crystallize for 3 h. Centrifuge to remove the mother liquor and dry in vacuum at 50 °C for 6 hours to obtain the crude product of zoledronic acid dimer, with a yield of 55.4%.

[0054] Add the crude product of zoledronic acid dimer and 1 L of purified water to a 5 L reaction flask in sequence, heat up to 70 °C, stir until completely dissolved, and continue to keep the temperature for 0.5 h. Cool the temperature to 30 °C, add 3.5 L of propanol, and start crystallization. Cool the temperature to 10 °C and keep the temperature for crystallization for 5 h. Centrifuge to remove the mother liquor and dry in vacuum at 50 °C for 6 hours to obtain the finished product of zoledronic acid dimer, with a yield of 82.7% and an HPLC purity of 97.4%.

[0055] Example 4

[0056] Ethylsulfonic acid (163 ml), phosphorus oxychloride (1 mol, 153.3 g), and imidazole-1-acetic acid (1 mol, 126.1 g) were successively added to a 5 L reaction flask, and the mixture was stirred until completely dissolved. The temperature was raised to 65 °C for reaction. After detecting that the reaction was complete, the temperature was lowered to 20 °C, 2 L of purified water was added, and the mixture was stirred for 0.5 h. Then, a 10 mol / L sodium hydroxide solution was added to adjust the pH to 2 - 3, and a solid was precipitated. Stirring for crystal precipitation was continued for 3 h. The product was centrifuged and dried in vacuo at 50 °C for 6 h to obtain the crude product of zoledronic acid dimer with a yield of 48.8%.

[0057] The crude product of zoledronic acid dimer and 1 L of purified water were successively added to a 5 L reaction flask. The temperature was raised to 70 °C and stirred until completely dissolved, and the temperature was maintained for 0.5 h. The temperature was lowered to 30 °C, 1 L of ethanol was added, and crystallization began. The temperature was lowered to 5 °C and crystallization was carried out while maintaining the temperature for 2 h. The product was centrifuged and dried in vacuo at 50 °C for 6 h to obtain the finished product of zoledronic acid dimer with a yield of 82.5% and an HPLC purity of 96.3%.

Claims

1. A method for preparing a zoledronic acid dimer represented by formula I, characterized in that, The preparation method comprises the steps described as follows: A. Dissolve imidazole-1-acetic acid in a sulfonic acid solvent, add a phosphorylation reagent to carry out a phosphorylation reaction, and hydrolyze the product obtained from the phosphorylation reaction. After the reaction is completed, adjust the pH, keep warm for crystallization, filter and dry to obtain a crude product of zoledronic acid dimer; B. Recrystallize the crude product to obtain a finished product of zoledronic acid dimer; 2. The preparation method of the zoledronic acid dimer according to claim 1, characterized in that The sulfonic acid solvent described in step A is selected from one of C 1-6 alkyl sulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

3. The preparation method of the zoledronic acid dimer according to claim 1, characterized in that, In step A, the molar ratio of the fed imidazole-1-acetic acid, sulfonic acid solvent, and phosphorylation reagent is 1:2-8:1-5.

4. The preparation method of the zoledronic acid dimer according to claim 1, characterized in that, The phosphorylation reagent described in step A is selected from one of phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorous acid, and phosphoric acid.

5. The preparation method of the zoledronic acid dimer according to claim 1, characterized in that, The hydrolysis treatment described in step A includes: the volume molar ratio of the added water to imidazole-1-acetic acid is 1:0.3-0.

6.

6. The preparation method of the zoledronic acid dimer according to claim 1, characterized in that, In step A, adjust the pH to 1.0-3.

0.

7. The preparation method of the zoledronic acid dimer according to claim 1, characterized in that, The recrystallization method in step B includes: dissolving the crude product of the compound shown in formula I in water and heating, keeping warm and stirring, then adding an alcohol solvent, keeping warm for crystallization, filtering and drying to obtain a finished product of zoledronic acid dimer.

8. The preparation method of the zoledronic acid dimer according to claim 1, wherein The alcohol solvent is selected from one of methanol, ethanol, and propanol.

9. The preparation method of the zoledronic acid dimer according to claim 1, wherein The feeding volume ratio of the water to the alcohol solvent is 1:1-3.

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