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Preparation method of sodium ibandronate

A technique for sodium ibandronate and a synthetic method, which is applied in the field of drug synthesis technology, can solve problems such as low yield, many types of impurities of sodium ibandronate, and difficult reaction and stirring, so as to achieve good repeatability and avoid difficult reaction and stirring , the effect of facilitating industrial production

Inactive Publication Date: 2015-05-20
JIANGSU QINGJIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The purpose of the present invention is to provide a kind of preparation method of sodium ibandronate, to solve the technical problem that the sodium ibandronate synthesized by the existing method has many types of impurities, difficult reaction stirring and low yield

Method used

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  • Preparation method of sodium ibandronate
  • Preparation method of sodium ibandronate
  • Preparation method of sodium ibandronate

Examples

Experimental program
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Effect test

Embodiment 1

[0033] 1. Synthesis of pyrophosphate hydrochloride

[0034] Add 5.5kg of propionate hydrochloride and 5.2kg of phosphorous acid into the reaction kettle, stir and heat to 75-80°C, the solid melts and becomes transparent, stir vigorously, add 5.55L of phosphorus trichloride dropwise at 70-80°C for 1-2 hours, And a large amount of acid gas is released; after the dropwise addition, the solution solidifies slowly, and the stirring is stopped for 6 hours; TLC monitors, and the reaction is cooled to room temperature after the completion of the reaction. Proceed directly to the next step.

[0035] 2. Synthesis of Crude Sodium Ibandronate

[0036] Add 20L of purified water to the reaction kettle containing pyrophosphate hydrochloride, slowly raise the temperature to reflux; after reflux for 6-10 hours, cool down to room temperature, add dropwise 50% sodium hydroxide solution to pH = 4.1-4.8 (about 5L ), add activated carbon and stir at room temperature for 0.5 hours, and filter. Tr...

Embodiment 2

[0041] 1. Synthesis of pyrophosphate hydrochloride

[0042] Add 5.5kg of propionate hydrochloride and 5.2kg of phosphorous acid into the reaction kettle, stir and heat to 75-80°C, the solid melts and becomes transparent, stir vigorously, add 5.55L of phosphorus trichloride dropwise at 70-80°C for 1-2 hours, And a large amount of acid gas is released; after the dropwise addition, the solution solidifies slowly, and the stirring is stopped for 6 hours; TLC monitors, and the reaction is cooled to room temperature after the completion of the reaction. Proceed directly to the next step.

[0043] 2. Synthesis of Crude Sodium Ibandronate

[0044] Add 20L of purified water to the reaction kettle containing pyrophosphate hydrochloride, slowly raise the temperature to reflux; after reflux for 6-10 hours, cool down to room temperature, add dropwise 50% sodium hydroxide solution to pH = 4.1-4.8 (about 5L ), add activated carbon and stir at room temperature for 0.5 hours, and filter. Tr...

Embodiment 3

[0049] 1. Synthesis of pyrophosphate hydrochloride

[0050] Add 5.5kg of propionate hydrochloride and 5.2kg of phosphorous acid into the reaction kettle, stir and heat to 75-80°C, the solid melts and becomes transparent, stir vigorously, add 5.55L of phosphorus trichloride dropwise at 70-80°C for 1-2 hours, And a large amount of acid gas is released; after the dropwise addition, the solution solidifies slowly, and the stirring is stopped for 6 hours; TLC monitors, and the reaction is cooled to room temperature after the completion of the reaction. Go directly to the next step.

[0051] 2. Synthesis of Crude Sodium Ibandronate

[0052] Add 20L of purified water to the reaction kettle containing pyrophosphate hydrochloride, slowly raise the temperature to reflux; after reflux for 6-10 hours, cool down to room temperature, add dropwise 50% sodium hydroxide solution to pH = 4.1-4.8 (about 5L ), add activated carbon and stir at room temperature for 0.5 hours, and filter. Transfe...

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Abstract

The invention relates to a drug synthesis method, and in particular relates to a preparation method of sodium ibandronate. The preparation method comprises the following steps of: directly reacting 3-(N-methyl-N-n-amylamine) propionic hydrochloride, phosphorous acid with phosphorus trichloride to obtain 1-hydroxyl-3-(methyl amylamine)-dimethylmethane-1,1-bipyrophosphoric acid hydrochloride, directly forming salt with sodium hydroxide after hydrolyzing so as to obtain crude sodium ibandronate, and respectively re-crystallizing for one time through mixed solvents of ethanol and water and acetone and water so as to obtain sodium ibandronate. Any solvent is not used in the step of synthesizing pyrophosphoric acid hydrochloride; solid-liquid reaction is carried out without stirring and post-treatment; products are directly used in the next step; a reaction system is dispersed by using organic solvents, such as chlorobenzene and diethyl carbonate, in some reported methods; products are shaped as oil blocks and are not beneficial to stirring and post-treating after reacting; in contrast, the kinds of impurities in the products are reduced; toxicity due to the organic solvents, such as chlorobenzene and diethyl carbonate, is eliminated; furthermore, the stirring difficulty is avoided; sodium ibandronate is prevented from being stuck on a stirrer and a bottle wall; and thus, industrial production is conveniently carried out.

Description

technical field [0001] The invention relates to a synthesis process of a bulk drug, in particular to a synthesis process of sodium ibandronate, and belongs to the field of pharmaceutical synthesis processes. Background technique [0002] Bisphosphonates are a new class of anti-metabolic bone disease drugs developed in the past 20 years. They are used to treat osteoporosis, osteitis deformans, hypercalcemia and bone pain caused by bone metastasis of malignant tumors etc., the application prospect is very broad. [0003] Ibandronate Sodium (Ibandronate Sodium) is a new generation of bisphosphonate drugs following Neridronate Sodium, Opadronate Sodium and Risedronate Sodium. It is the latest generation of bisphosphonate drugs. It has the advantages of high efficiency, low toxicity and convenient use, and has two dosage forms, oral and intravenous. [0004] Ibandronic acid sodium chemical name: [1-hydroxy-3-(N-methyl-N-pentylamino) propylene] bisphosphonic acid monosodium salt...

Claims

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Application Information

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IPC IPC(8): C07F9/38
Inventor 王栋汪武卫刘兴超
Owner JIANGSU QINGJIANG PHARMA
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