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Preparation method for sodium zoledronic acid

A technology of sodium zoledronic acid and zoledronic acid, which is applied in the field of drug synthesis, can solve problems such as the residual amount of organic solvents easily exceeding the standard, unfavorable industrial production, and non-compliance with pharmaceutical standards, and achieves easy separation and purification and high yield , post-processing convenient effect

Inactive Publication Date: 2015-05-13
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In the prior art, the reaction conditions of the synthetic method of sodium zoledronic acid are relatively harsh, and more toxic methanol, chloroform and chlorobenzene are used, and the residual organic solvent is easily exceeded, the yield is low, the product purity is low, pollutes the environment, and does not Conforms to medicinal standards and is not conducive to industrial production

Method used

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  • Preparation method for sodium zoledronic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of Sodium Zoledronate

[0026]

[0027] (1) Synthesis of ethyl imidazol-1-yl acetate

[0028] Add imidazole (13.62g, 0.2mol) and [bmim]BF in turn to the three-neck flask 4 (100mL), stir and heat up to 60°C, under reflux, slowly add ethyl chloroacetate (24.51g, 0.2mol) dropwise, the dropwise addition time is about 2h, keep stirring under reflux for 16h, TLC monitors the end point of the reaction and shows There was no raw material point, the reaction was completed, and the temperature was lowered to room temperature to obtain a crude product of ethyl imidazol-1-yl acetate, about 24 g, which was directly used in the next reaction without further purification.

[0029] (2) Synthesis of imidazol-1-ylacetic acid hydrochloride

[0030] Add 24g of the crude ethyl imidazol-1-yl acetate prepared above into a three-necked flask, add concentrated hydrochloric acid (34mL), heat up to 85°C with exotherm, continue to heat up to reflux, stir and react under reflux f...

Embodiment 2

[0036] Influence of Phosphorus Trichloride Adding Time on Reaction Yield

[0037] Fix other conditions unchanged, only change the rate of addition of phosphorus trichloride, the impact of rate of addition on the yield of sodium zoledronic acid is shown in Table 1, and the test results show that when phosphorus trichloride is added dropwise too fast, a large amount of gas will be produced instantaneously , the reaction is very intense, the liquid splashes, and the temperature rises rapidly, resulting in a low yield. If it is added dropwise slowly, the reaction speed is too slow and the consumption time is too long, so 4h is the best dropwise addition time.

[0038] Dropping time (h) Yield (%) 2.5 51.7 3.5 71.6 4.0 90.1 4.5 90.1 5.5 88.5

Embodiment 3

[0040] Effect of Reaction Temperature on the Yield of Sodium Zoledronate

[0041] With other conditions kept constant, the effect of the reaction temperature of the condensation of imidazol-1-ylacetic acid hydrochloride with phosphoric acid and phosphorus trichloride on the yield of zoledronic acid monohydrate, the results are shown in Table 2. The test results show that as the temperature increases, the yield increases gradually, but when the reflux temperature is high, the yield shows a downward trend, which is due to the decomposition of phosphorus trichloride, resulting in a decrease in reactants. In addition, when the temperature is too high, the loss of solvent volatilization and solvent leakage will inevitably increase. When the reflux temperature is low, the reaction rate is slow and the reaction is insufficient, so the yield is low. Therefore, the optimal reaction temperature is about 65 ° C.

[0042] temperature (°C) Yield (%) 55 63.4 60 78.5 ...

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Abstract

The invention discloses a preparation method for sodium zoledronic acid, and belongs to the technical field of medicine synthesis. The technical scheme key point is that the preparation method for sodium zoledronic acid comprises the following steps: using a reaction medium as an ionic liquid, using imidazole-1-group acetic acid hydrochloride as a raw material, condensing with phosphoric acid and phosphorus trichloride, then hydrolyzing to prepare zoledronic acid monohydrate, and then carrying out reaction between zoledronic acid monohydrate and sodium hydroxide for salification so as to obtain the sodium zoledronic acid, wherein the ionic liquid is 1-n-butyl-3-methyl imidazolium tetrafluoroborate, N-ethyl pyridine tetrafluoroborate, 1-n-butyl-3-methyl imidazolium hexafluorophosphate, 1-ethoxyl-2,3-dimethyl imidazolium chloride, 1-nitrile propyl-3-methyl imidazolium chloride or 1-carboxyethyl-3-methyl imidazolium chloride. The preparation method has the advantages that the raw materials are highly available; the operation is simple and convenient; the yield and the product purity are high; the requirements of environmental protection and medicine production are met; the suitability for industrialized production is realized.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of zoledronic acid sodium. Background technique [0002] Zoledronate sodium (Zoledronate sodium, Ⅰ), the chemical name is [1-hydroxy-2-(1H-imidazol-1-yl) ethylidene] diphosphonic acid monosodium salt monohydrate, which is produced by Novartis, Switzerland. The imidazole heterocyclic bisphosphonate developed by (Novartis) belongs to the third generation of bisphosphonate drugs and was first listed in Canada in October 2000. Subsequently, it was approved in more than 80 countries or regions including the European Union and the United States. The trade name is Zometa, which is used for the treatment of hypercalcemia (HCM) caused by malignant tumors, multiple myeloma and bone metastases of solid tumors. The drug can effectively treat HCM caused by malignant tumors, advanced tumor bone metastasis and osteitis deformans, reduce the occurrence of...

Claims

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Application Information

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IPC IPC(8): C07F9/6506
Inventor 郝二军蒋小涵刘玉侠张倩王东超谢明胜王海霞郭海明李恭新
Owner HENAN NORMAL UNIV
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