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Preparation method of ibandronate sodium

A technology of sodium ibandronate and propionate hydrochloride is applied in the field of synthesis technology of sodium ibandronate, which can solve the problems of high safety, difficulty in stirring, hidden danger and the like, and achieves low cost, good product quality and safety. high effect

Inactive Publication Date: 2014-05-07
LIAONING CHENGDA BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Through experiments, we found that although methanesulfonic acid as a solvent can better solve the problem of difficult stirring, but the reaction has a greater safety hazard

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0029] In a 250ml four-necked bottle equipped with a thermometer, mechanical stirring, a constant pressure dropping funnel and an exhaust gas absorption device, add 5.0 g of 3-(N-methyl-N-n-pentylamino) propionate hydrochloride, phosphorous acid 4.0g, propylene glycol carbonate 25.0g, start stirring, add 11.0g of phosphorus trichloride dropwise under the condition of 15-25°C, control the temperature of the reaction solution not to exceed 60°C during the dropwise addition. The temperature of the solution is raised to 60-70°C, and the reaction is kept for 3-4 hours. It is observed that no sticky lumps appear in the reaction solution. When the temperature is lowered to 30-40°C, 25.0g of purified water is added dropwise, and the temperature of the reaction solution is controlled not to exceed 70°C, heat up to 80-90°C for 3-4 hours, lower to 20-30°C, add about 30ml of 50% sodium hydroxide aqueous solution to adjust the pH to 4.0-4.5, add 80.0g of ethanol at 15-25°C Stir for 12 hour...

Embodiment 2

[0036] In a 250ml four-necked bottle equipped with a thermometer, mechanical stirring, a constant pressure dropping funnel and an exhaust gas absorption device, add 5.0 g of 3-(N-methyl-N-n-pentylamino) propionate hydrochloride, phosphorous acid 4.9g, propylene carbonate 40.0g, start stirring, add 11.0g of phosphorus trichloride dropwise at 15-25°C, control the temperature of the reaction solution not to exceed 60°C during the dropwise addition, and react The temperature of the solution is raised to 60-70°C, and the heat preservation reaction is carried out for 3-4 hours. It can be observed that no sticky lumps appear in the reaction solution. When it drops to 30-40°C, 25.0g of purified water is added dropwise, and the temperature of the reaction solution is controlled during the dropwise addition. When it exceeds 70°C, heat up to 80-90°C for 3-4 hours to hydrolyze, then drop to 20-30°C, add about 30ml of 50% sodium hydroxide aqueous solution to adjust the pH to 4.0-4.5, add 80...

Embodiment 3

[0043] In a 250ml four-necked bottle equipped with a thermometer, mechanical stirring, a constant pressure dropping funnel and an exhaust gas absorption device, add 5.0 g of 3-(N-methyl-N-n-pentylamino) propionate hydrochloride, phosphorous acid 4.9g, propylene carbonate 50.0g, start stirring, add 20.7g of phosphorus trichloride dropwise at 15-25°C, control the temperature of the reaction solution not to exceed 60°C during the dropwise addition, and react The temperature of the solution is raised to 60-70°C, and the heat preservation reaction is carried out for 3-4 hours. It can be observed that no sticky lumps appear in the reaction solution. When it drops to 30-40°C, 25.0g of purified water is added dropwise, and the temperature of the reaction solution is controlled during the dropwise addition. When the temperature exceeds 70°C, heat up to 80-90°C for 3-4 hours for hydrolysis, then drop to 20-30°C, add about 50ml of 50% sodium hydroxide aqueous solution to adjust the pH to ...

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Abstract

The invention discloses a preparation method of ibandronate sodium, which is characterized in that: adding 3-(N-methyl-N-pentylamino) propionic acid hydrochloride, phosphorous acid, inertia solvent and phosphorus trichloride; carrying out a condensation reaction at 40-80 DEG C for 2-6 hours; adding purified water for 2-6 hours of hydrolysis for generating ibandronate sodium; carrying out a salt forming reaction with sodium hydroxide, and obtaining the ibandronate sodium crude product; recrystallizing the crude product with a mixed solvent containing acetone and water, and obtaining the ibandronate sodium. According to the invention, the added solvent is propylene carbonate, by using the solvent, the reaction resultants can be uniformly dispersed in the solvent, and thereby overcoming the disadvantages that products with viscosity are generated in the reaction by using other solvents, and the products are not easy to be stirred and the reaction is not easy to controlled; and the propylene carbonate has little toxicity; the invention has the advantages of simple operation, high safety, good product quality, low cost, etc. The preparation method is convenient for large scale production.

Description

technical field [0001] The invention relates to a drug synthesis process, in particular to a synthesis process involving ibandronate sodium, and belongs to the technical field of drug synthesis process. Background of the invention [0002] Sodium ibandronate, the chemical name is [1-hydroxy-3-(N-methyl-N-pentylamino) propylene] bisphosphonic acid monosodium salt monohydrate, English name: Sodium Ibandronate;[ 1-hydroxy-3-(N-methyl-N-pentylaino)propylidene] bisphosphonic acid monosodium salt, CAS number: 138926-19-9, molecular formula: C 9 h 22 NNaO 7 P 2 ·H 2 O. [0003] Bisphosphonates are a new generation of drugs developed in the past 30 years. They are used for the treatment and prevention of bone metastasis of malignant tumors, osteoporosis, abnormal acceleration of bone renewal metabolism, etc., and their application prospects are very broad. [0004] Ibandronate Sodium is the latest generation of bisphosphonate drugs, which is the third generation. It was develo...

Claims

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Application Information

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IPC IPC(8): C07F9/38
Inventor 高军张庆义赵会林杜国新朱君李欣禹刘宝珠刘晓颖
Owner LIAONING CHENGDA BIOTECH
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