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Preparation method of zoledronic acid intermediate impurity

A technology for zoledronic acid and intermediates, which is applied in the field of preparation of zoledronic acid intermediate impurity 1-acetic acid-3-acetoxyimidazolium salt, and can solve problems such as low work efficiency, unsuitability for industrialization, and poor economy , to achieve the effect of ensuring safety and effectiveness, simple and easy preparation method, ideal yield and purity

Pending Publication Date: 2022-02-18
CHANGZHOU FANGYUAN PHARMA +1
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Problems solved by technology

[0004] With the advancement of the country's drug consistency work, determining the preparation method of each impurity compound and providing qualified reference substances can play a more active role in the quality control of zoledronic acid raw materials, but the current economical and fast 1 -The synthetic method of acetic acid-3-acetoxyimidazolium salt is rarely reported
[0005] Chao Ma (Chao Ma, Jiayun Li, Jiajian Peng, et al. Effect of carboxyl-functionalized imidazolium salts on the rhodium-catalyzed hydrosilylation ofalkene[J].Journal of Organometallic Chemistry, 727, 2013:28-36) and Jian Sun ( Jian Sun, Lijun Han, Weiguo Cheng, et al. Efficient Acid-Base BifunctionalCatalysts for the Fixation of CO2 with Epoxides under Metal- and Solvent-FreeConditions[J]. ChemSusChem 2011: 502–507.) et al. Silicon-based imidazole is used as a starting material, and this type of method has the disadvantages of poor economy and high cost
[0006] Huimin Luo et al. (Huimin Luo, Sheng Dai, Peter V. Bonnesen, et al. Separation of Fission Products Based on Room-Temperature Ionic Liquids [J]. American Chemical Society, 2006, 146-161.) used the dangerous reagent sodium hydride to remove Active hydrogen on imidazole, and then carry out nucleophilic substitution reaction, this method has the disadvantages of high safety risk, not suitable for industrial production, etc.
[0007] Yuan Yuan (Master's thesis of Jilin University "Determination of Zoledronic Acid Content and Research on Related Substances") used relatively expensive alkyl bromoacetate to introduce acetic acid groups, and column chromatography was required for separation and purification, which was economical and labor-intensive. Low efficiency, not suitable for industrialization and other shortcomings

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  • Preparation method of zoledronic acid intermediate impurity
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  • Preparation method of zoledronic acid intermediate impurity

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[0036] The present invention prepares the preparation method of zoledronic acid intermediate impurity 1-acetic acid-3-acetoxy imidazolium salt comprising the following steps:

[0037] ① Nucleophilic substitution. Add imidazole and solvent into the reaction bottle, stir to dissolve, add metal iodide and alkali into the bottle, stir at 0°C-40°C for 1-3 hours; then add haloacetate into the reaction bottle, The reaction is stirred and reacted at ~40°C for 20-40 hours, and the reaction liquid is obtained after the reaction is completed, the reaction liquid is filtered, and the filtrate is concentrated.

[0038] The solvent is one or a mixture of tetrahydrofuran, 1,4-dioxane and dichloromethane.

[0039] The metal iodide is sodium iodide and / or potassium iodide. The amount of metal iodide is 0.01 to 0.1 times that of imidazole.

[0040] The alkali is one or a mixture of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bic...

Embodiment 1）

[0048] In this embodiment, the reaction formula for preparing the zoledronic acid intermediate impurity 1-acetic acid-3-acetoxy imidazolium salt is as follows:

[0049] .

[0050] The preparation method of the zoledronic acid intermediate impurity 1-acetic acid-3-acetoxy imidazolium salt of the present embodiment comprises the following steps:

[0051] ① Nucleophilic substitution. Add 20.0g (0.29mol) of imidazole and 160mL of dichloromethane into a 500mL four-neck flask, stir and dissolve; add 60.9g (0.44mol) of potassium carbonate and 2.2g (0.015mol) of sodium iodide into the bottle, Stir at 30°C for 1±0.5 hours; then add 63.8g (0.59mol)) of methyl chloroacetate into the bottle, stir and react at 20°C to 40°C for 24±0.5 hours, stop the reaction to obtain a reaction solution. The reaction solution was filtered, and the filtrate was concentrated to 20%-40% of the original volume (25% in this example) by rotary evaporation under reduced pressure to obtain a concentrated solu...

Embodiment 2）

[0063] This embodiment prepares the preparation method of zoledronic acid intermediate impurity 1-acetic acid-3-acetoxyimidazolium salt and the rest is the same as Example 1, the difference is:

[0064] The alkali that adds in the step 1. is 0.44mol sodium hydroxide; The iodide that adds is 0.025mol potassium iodide.

[0065] After adding water to the concentrated solution in step ②, stir and react at 90°C to 100°C for 5±0.5 hours; after the reaction, pour the reaction solution into 300mL tetrahydrofuran to disperse, and filter to obtain the crude product.

[0066] Step ③ After beating and purifying in a mixed solvent (tetrahydrofuran: water = 4:1), 30.9 g (0.17 mol) of 1-acetate-3-acetoxyimidazolium salt was obtained, with a molar yield of 57.9% and a purity of 99.2% by HPLC.

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Abstract

The invention discloses a preparation method of a zoledronic acid intermediate impurity. The preparation method comprises the following steps: (1) nucleophilic substitution: dissolving imidazole, adding metal iodide and alkali, adding halogenated acetate into a reaction system, carrying out filtering after reaction, and concentrating a filtrate; (2) hydrolysis: adding water into a concentrated solution obtained in the step (1) for hydrolysis, dispersing a hydrolysis product, and carrying out filtering to obtain a crude product; and (3) purification: pulping and purifying the crude product obtained in the step (2) to obtain a target compound. According to the invention, a nucleophilic substitution and a hydrolysis reaction are conducted in one pot, separation and purification are not needed in the process, and only an organic / inorganic mixed solvent is used for pulping and purification finally, so the preparation method is simple and easy to implement, yield and purity are ideal, a structural formula is correct, and the intermediate impurity can be prepared on a large scale. The impurity is used as an impurity reference substance in a zoledronic acid synthesis process, so the condition of diacetoxy reaction impurities in zoledronic acid synthesis is reasonably and effectively controlled, and the safety and effectiveness of zoledronic acid bulk drugs are finally ensured.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of zoledronic acid intermediate impurity 1-acetic acid-3-acetoxyimidazolium salt. Background technique [0002] Zoledronic acid (zoledronic acid) is a heterocyclic third-generation bisphosphonic acid drug for the treatment of hypercalcemia, the chemical name is 1-hydroxy-2-(1-imidazolyl)ethylene-1,1- diphosphoric acid. Compared with first-generation bisphosphonates (clomedronate, etidronate) and second-generation bisphosphonates (tiludronate, pamidronate) Good titer strength, long action time, and small dosage. Zoledronic acid, as a bisphosphonic acid compound that specifically acts on bone, can inhibit bone resorption caused by increased osteoclast activity, but has no adverse effects on bone formation, mineralization, and mechanical properties. It is used to treat hypercalcemia caused by tumor (TIH or HCM), inhibit bone metastasis caused by...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/56
CPCC07D233/56
Inventor 印靖金敏王海东王凯耿贺贺苏晓春
Owner CHANGZHOU FANGYUAN PHARMA
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