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Method for preparing Alendronic acid

A technology of alendronic acid and phosphorous acid is applied in the field of preparation of alendronic acid, which can solve the problems of uneconomical, unsuitable for industrial production, out of control of self-exothermic punching, etc., and achieves improved safety and good industrial application prospects. Effect

Inactive Publication Date: 2005-08-31
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The solvent chlorobenzene is cheap, and the cost of raw materials is relatively low, but this process has serious safety problems of charging. When the reaction temperature exceeds 85°C, it is prone to self-accelerating exothermic action and out of control, thus breaking out of charging; US Patent US 4 705 651 Using excess phosphorus trichloride and phosphorous acid as solvent, react with γ-aminobutyric acid, phosphorous acid and phosphorus trichloride, and then obtain alendronic acid through subsequent reaction
The reactant as the solvent is greatly excessive, and the solvent is difficult to recycle, so the cost is too high, it is not suitable for industrial production, and the solvent cannot stably control the reaction temperature; U.S. Patent US 4 922 007 uses methanesulfonic acid as a solvent, and is also composed of γ-amino Butyric acid, phosphorous acid, phosphorus trichloride reaction, and then through the subsequent reaction to get alendronic acid
This process uses high-priced methanesulfonic acid as a solvent, which is neither economical nor easy to recycle. It not only affects the purity of the product but also brings certain troubles to environmental protection, and the solvent cannot stably control the reaction temperature.
In addition, in the case of scale-up, these three process routes all have a serious problem of self-exothermic punching out of control, which is never allowed in industrial production.

Method used

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  • Method for preparing Alendronic acid

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Experimental program
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Effect test

Embodiment 1

[0017] Add γ-amino acid and phosphorous acid with a molar ratio of 1:1.2 to cyclohexane that is 5 times the weight of γ-amino acid, under stirring, heat the water bath to reflux, keep warm, and when the solution becomes translucent gel, start to drop Phosphorus trichloride corresponding to 1.2 equivalents of γ-amino acid was added. Stirring with heating was continued for 4 hours. Heating was stopped, cooled to room temperature, and the solvent was removed by filtration; then an appropriate amount of distilled water was added to dissolve the jelly, and heating was continued under reflux for 1 hour. Use activated carbon to decolorize, filter to obtain a clear and colorless solution, concentrate under reduced pressure, and after cooling, add the concentrated solution dropwise to an appropriate amount of hot methanol (50°C) with stirring to produce a white precipitate, which is separated by filtration after cooling to obtain alendronic acid White crystalline powder, m.p.229°C, yi...

Embodiment 2

[0019] Add γ-amino acid and phosphorous acid with a molar ratio of 1:1.4 to benzene that is 5 times the weight of γ-amino acid, under stirring, heat in a water bath to reflux, keep warm, and after the solution is translucent gelatinous, start to drop an equivalent amount of Phosphorus trichloride in 1.2 equivalents of γ-amino acids. Stirring with heating was continued for 3.5 hours. Heating was stopped, cooled to room temperature, and the solvent was removed by filtration; then an appropriate amount of distilled water was added to dissolve the jelly, and heating was continued under reflux for 1 hour. Use activated carbon to decolorize, filter to obtain a clear and colorless solution, concentrate under reduced pressure, and after cooling, add the concentrated solution dropwise to an appropriate amount of hot methanol (50°C) with stirring to produce a white precipitate, which is separated by filtration after cooling to obtain alendronic acid White crystalline powder, m.p.229°C,...

Embodiment 3

[0021] Add γ-amino acid and phosphorous acid with a molar ratio of 1:1.3 to n-hexane that is 5 times the weight of γ-amino acid, under stirring, heat to reflux in a water bath, keep warm, and start adding dropwise after the solution becomes translucent gel Phosphorus trichloride equivalent to 1.2 equivalents of γ-amino acids. Stirring with heating was continued for 8 hours. Heating was stopped, cooled to room temperature, and the solvent was removed by filtration; then an appropriate amount of distilled water was added to dissolve the jelly, and heating was continued under reflux for 1 hour. Use activated carbon to decolorize, filter to obtain a clear and colorless solution, concentrate under reduced pressure, and after cooling, add the concentrated solution dropwise to an appropriate amount of hot methanol (50°C) with stirring to produce a white precipitate, which is separated by filtration after cooling to obtain alendronic acid White crystalline powder, m.p.229°C, yield 57...

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Abstract

A process for preparing Alunphosphonic acid includes such steps as reflux reaction between gamma-aminobutanoic acid, PCl3, and phosphorous acid in the inertial solvent whose boiling point is 50-90 deg.C, and post-treating. Its reaction temp can be controlled well.

Description

(1) Technical field [0001] The invention relates to a preparation method of alendronic acid. (2) Background technology [0002] Osteoporosis has brought great suffering to countless elderly patients and their families, which has attracted the attention of the whole society. As early as the 1970s, some people began to use bisphosphonates to treat osteoporosis. In the 1980s, they were systematically used in clinical practice and gradually became an important class of drugs for the prevention and treatment of osteoporosis. Alendronate sodium (Alendronate sodium) is a third-generation bisphosphonate on the market for the treatment of osteoporosis, and is a new type of highly effective bone resorption inhibitor. The reaction formula of the precursor alendronic acid of synthetic preparation alendronic acid sodium is as follows: [0003] [0004] U.S. Patents US 4 407 761 and US 4 621 077 use chlorobenzene as a solvent, γ-aminobutyric acid, phosphorous acid, and phosphorus tri...

Claims

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Application Information

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IPC IPC(8): C07F9/38
Inventor 李景华焦丹王耀军
Owner ZHEJIANG UNIV OF TECH
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