Process for preparing dazoline phospho acid

A technology for zoledronic acid and imidazole, which is applied in the field of one-step synthesis of zoledronic acid, can solve problems such as methods to be improved, and achieve the effects of low cost, high safety and simplified operation

Inactive Publication Date: 2005-11-09
YANGTZE RIVER PHARM GRP CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, the above literatu

Method used

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Embodiment 1

[0013] Example 1: 500 mL of 1,4-dioxane and 40 g of 60% sodium hydride were added to a reaction flask, and a solution of 68 g of imidazole in 150 mL of 1,4-dioxane was added dropwise with stirring in an ice-water bath. After dropping, stir at room temperature for 30 minutes, add 122.5 g of ethyl chloroacetate dropwise, and react with stirring at room temperature for 3 hours. Slowly add 200mL of 85% phosphoric acid, raise the temperature to 50°C-60°C and react for 4 hours, add 200mL of phosphorus trichloride dropwise at this temperature, control the rate of addition, and drop it in about 1 hour. Heat up to reflux for 4 hours, cool to 50°C-60°C, add 500 mL of 6mol / L hydrochloric acid, heat up to reflux for 3 hours. Cool, crystallize under stirring, collect the precipitated solid by filtration, wash with a small amount of ethanol, and recrystallize in distilled water to obtain 93 g of zoledronic acid, yield: 32.0% mp: 239°C (decomposition).

[0014] Elemental analysis (C 5 h 1...

Embodiment 2

[0017] Example 2: Add 68g of imidazole, 120g of potassium carbonate, 700mL of 1,4-dioxane, and 76g of chloroacetonitrile into the reaction flask, stir and react at room temperature for 24 hours, remove insoluble matter by filtration, add 200mL of 85% phosphoric acid to the filtrate, and stir to raise the temperature React at 50°C-60°C for 4 hours, add phosphorus trichloride 200mL dropwise at this temperature, control the rate of addition, and drop it in about 1 hour. Heat up to reflux for 4 hours, cool to 50°C-60°C, add 500 mL of 6mol / L hydrochloric acid, heat up to reflux for 3 hours. Cool, crystallize under stirring, collect the precipitated solid by filtration, wash with a small amount of ethanol, and recrystallize in distilled water to obtain 87 g of zoledronic acid, yield: 29.9% mp: 239°C (decomposition).

[0018] Elemental analysis (C 5 h 10 N 2 o 7 P 2 h 2 O): The theoretical value (%) is C20.70, H4.17, N9.66, P21.53; the experimental value (%) is C20.80, H4.20, N...

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Abstract

A process for preparing Zuolailingsuan from imidazole includes such steps as reaction between imidazole and alpha-haloacetate or alpha-haloacetonitrile in inertial solvent under catalysis of alkali, hydrolyzing in phosphoric acid solution, reacting on phosphorus trichloride (or trioxychloride), acidic hydrolyzing, and recrystallizing in distilled water.

Description

technical field [0001] The invention relates to a preparation method for one-step synthesis of zoledronic acid by using imidazole as a starting material. Background technique [0002] Zoledronic acid, whose chemical name is [1-hydroxy-2-(1-imidazolyl) ethylidene] diphosphate monohydrate, is a heterocyclic third-generation bisphosphonic acid drug for the treatment of hypercalcemia. The drug can reduce the incidence of bone and soft tissue metastasis in cancer patients. It can be used as an adjuvant treatment for cancer patients with bone metastasis to relieve hypercalcemia, bone pain and the risk of fractures. It can also be used to delay the occurrence of bone metastasis. Its mechanism of action is to inhibit bone metastasis. Absorption reduces the release of bone matrix growth factors or inhibits cancer cells from adhering to the bone matrix. Clinical trials have shown that this product is the strongest bisphosphonate compound so far. In 2000, zoledronic acid was first ap...

Claims

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Application Information

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IPC IPC(8): C07F9/6506
Inventor 蔡伟张玉斌曹燕锋刘江华戚苏明王喜习尹必喜
Owner YANGTZE RIVER PHARM GRP CO LTD
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