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Method for preparing sodium Ibandronate monohydrate

A technology of sodium ibandronate and monohydrate, which is applied in the field of preparation of sodium ibandronate monohydrate, can solve the problems of extremely high equipment and environmental requirements, unsuitability for industrial production, difficult operation, etc., and achieve the goal of reaction process Safe and reliable, easy to industrialized production, good reaction selectivity effect

Active Publication Date: 2014-02-05
ANHUI PIOM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] All the routes mentioned above, our researchers, after a lot of experiments and explorations, found that the yield is extremely low, the operation is difficult, the requirements for equipment and the environment are extremely high, and they are not suitable for industrial production at all.

Method used

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  • Method for preparing sodium Ibandronate monohydrate
  • Method for preparing sodium Ibandronate monohydrate
  • Method for preparing sodium Ibandronate monohydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] 1) A 50L dry and clean double-layer glass reaction kettle is connected to a hydrochloric acid gas absorption device, and at 25-30°C, add 3kg (14.3mol) of 3-[methyl(pentyl)amino]propionate and 4.4kg of phosphorous acid (53.57mol) and DMI9L, stir for 10min, drop in phosphorus trichloride, control the system temperature at 60-70°C, after the drop-in is complete, raise the temperature to 80°C for 6h, cool to 30°C, drop in 20L of deionized water, control The temperature of the system is < 45°C, after the drop is completed, heat and stir until reflux, the temperature is 110°C, react for 7 hours, TLC controls the end point (developing agent: water-glacial acetic acid-n-butanol=1:1:3), the reaction is complete, Cool to 40°C, add 30% sodium hydroxide solution dropwise to adjust the pH to 4.1-4.3, add 20L of methanol, stir for 2 hours, centrifuge and filter, wash the solid with 2L of methanol, and dry under reduced pressure at 55-60°C to obtain ibandronic acid as a white solid So...

Embodiment 2

[0069] 1) A 50L dry and clean double-layer glass reaction kettle is connected to a hydrochloric acid gas absorption device, and at 25-30°C, add 3kg (14.3mol) of 3-[methyl(pentyl)amino]propionate and 4.4kg of phosphorous acid (53.57mol) and DMI12L, stir for 10min, drop in phosphorus trichloride, control the system temperature at 60-70°C, after the drop-in is completed, raise the temperature to 80°C for 6h, cool to 30°C, drop in 20L of deionized water, control The temperature of the system is < 45°C, after the drop is completed, heat and stir until reflux, the temperature is 110°C, react for 7 hours, TLC controls the end point (developing agent: water-glacial acetic acid-n-butanol=1:1:3), the reaction is complete, Cool to 40°C, add 30% sodium hydroxide solution dropwise to adjust the pH to 4.1-4.3, add 20L of methanol, stir for 2 hours, centrifuge and filter, wash the solid with 2L of methanol, and dry under reduced pressure at 55-60°C to obtain ibandronic acid as a white solid ...

Embodiment 3

[0073] 1) A 50L dry and clean double-layer glass reaction kettle is connected to a hydrochloric acid gas absorption device, and at 25-30°C, add 3kg (14.3mol) of 3-[methyl(pentyl)amino]propionate and 4.4kg of phosphorous acid (53.57mol) and DMI3L, stir for 10min, add 12L of toluene, drop in phosphorus trichloride, control the temperature of the system at 60-70°C, after the addition is complete, raise the temperature to 80°C for 7h, cool to 30°C, and discard the organic layer , the residue was dropped into 20L of deionized water, and the temperature of the system was controlled at <45°C. After the drop was completed, heated and stirred to reflux at a temperature of 105°C, reacted for 5h, and controlled the end point by TLC (developing agent: water-glacial acetic acid-n-butanol =1:1:3), after the reaction is completed, cool to 40°C, add dropwise 30% sodium hydroxide solution to adjust the pH to 4.1~4.3, add 20L methanol, stir for 2h, centrifuge, wash the solid with 2L methanol, 55...

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Abstract

The invention belongs to the field of medicine chemistry synthesis, and relates to a method for preparing a sodium Ibandronate monohydrate. The method comprises that: 1) 3-(N-methylpentylamino)propanoic acid hydrochloride, phosphorous acid and phosphorus trichloride are adopted as starting raw materials and are subjected to a reaction in a 1,3-dimethyl-2-imidazolidinone (DMI) solvent or a DMI-containing mixing solvent to obtain the sodium Ibandronate monohydrate crude product meeting the internal control standard in the one-step manner; and 2) the sodium Ibandronate monohydrate crude product is subjected to recrystallizatio in a methanol / water mixing solvent to obtain the sodium Ibandronate monohydrate meeting the clinical medicinal standard. According to the present invention, defects of low yield, high reagent toxicity, heavy pollution and the like in the prior art are overcome, and the preparation method for the sodium Ibandronate monohydrate represented by the formula (I) is provided, wherein the preparation method has characteristics of high yield, low environmental pollution, and easy purification.

Description

1. Technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and more specifically relates to a preparation method of ibandronic acid sodium monohydrate. 2. Background technology [0002] Ibandronate sodium (Ibandronate, formerly code-named BONIVA), is a third-generation bisphosphonate drug, and is currently the mainstream drug in the world for the prevention and treatment of bone metastasis of malignant tumors and the prevention and treatment of osteoporosis. The medicine has the advantages of high efficiency, low toxicity, convenient use and the like. Ibandronate sodium was first developed by Hoffmann-La Roche for the treatment of bone metabolism disorders, such as hypercalcemia caused by malignant tumors, osteolysis, Paget-like disease, osteoporosis and metastatic bone disease. Diseases, etc., can be made into intravenous or oral pharmaceutical preparations for use. At present, ibandronate sodium has been established as the standard...

Claims

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Application Information

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IPC IPC(8): C07F9/38
Inventor 徐奎陈正皓魏伟叶加久
Owner ANHUI PIOM PHARMA
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