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Synthetic method of clinic effect of alendronate

A technology for the synthesis of alendronic acid and its synthesis method, which is applied in the synthesis of compounds and the field of synthesis of alendronic acid, can solve the problems of chlorobenzene toxicity, environmental pollution, overheating of reaction, etc., achieve stable solvent properties, strong operability, easy separation effect

Active Publication Date: 2008-10-15
CSPC OUYI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existing problem is that as the reaction proceeds, the reaction mixture solidifies and cannot be stirred, resulting in local overheating of the reaction, and the decomposition of phosphorous acid to generate phosphine spontaneous combustion, causing safety hazards; and the uneven yield of the reaction is only about 40%.
However, the reaction process produces a viscous orange-yellow substance, which makes stirring difficult
And chlorobenzene has very strong toxicity, pollutes environment, has certain residue in alendronic acid
U.S. Patents US4922007 and US5019651 provide a method for preparing alendronic acid by reacting GABA with phosphorous acid and phosphorus trichloride using methanesulfonic acid as a solvent. Methanesulfonic acid has strong corrosiveness and irritation , whether it is used or in the process of producing methanesulfonic acid, it will cause serious pollution to the environment
In addition, methanesulfonic acid has a strong exothermic reaction with phosphorus trichloride, which may be dangerous in large-scale production
US Patent 20060293524A1 provides a method for producing alendronic acid using sulfolane as a solvent, but sulfolane is not easy to produce, and sulfolane partially decomposes during use, and the yield of alendronic acid is low, only about 76%

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] (a) Phosphonylation reaction: 10g of 4-aminobutyric acid, 16g of phosphorous acid, in the reaction flask, add 40ml of 1,3-dimethylimidazolinone to dissolve it, add dropwise 18ml of phosphorus trichloride, and then control Keep warm at 70-80°C for 5 hours.

[0019] (b) Hydrolysis reaction: heat filter the above reaction solution to filter out insoluble matter, then add 100ml of deionized water, heat up, and perform hydrolysis reaction at 100°C for 4 hours.

[0020] (c) Crystallization: lower the temperature, add 400 ml of ethanol to crystallize, filter, wash the filter cake with ethanol, and dry to obtain 24.52 g of dry product of alendronic acid, with a yield of 94.66%.

Embodiment 2

[0022] (a) Phosphonylation reaction: 10g of 4-aminobutyric acid, 16g of phosphorous acid, in the reaction flask, add 40ml of 1,3-diethylimidazolinone to dissolve it, add dropwise 18ml of phosphorus trichloride, and then control Keep warm at 70-80°C for 5 hours.

[0023] (b) Hydrolysis reaction: heat filter the above reaction solution to filter out insoluble matter, then add 100 ml of deionized water, heat up, and perform hydrolysis reaction at 100° C. for 4 hours.

[0024] (c) Crystallization: lower the temperature, add 400 ml of ethanol to crystallize, filter, wash the filter cake with ethanol, and dry to obtain 24.42 g of dry product of alendronic acid, with a yield of 94.27%.

Embodiment 3

[0026] (a) Phosphonylation reaction: 10g of 4-aminobutyric acid, 16g of phosphorous acid, in the reaction flask, add 40ml of 1,3-dipropylimidazolidinone to dissolve it, add dropwise 18ml of phosphorus trichloride, and then control Keep warm at 70-80°C for 6 hours.

[0027] (b) Hydrolysis reaction: heat filter the above reaction solution to filter out insoluble matter, then add 100 ml of deionized water, heat up, and perform hydrolysis reaction at 100° C. for 4 hours.

[0028] (c) Crystallization: cool down, add 400ml of ethanol to crystallize, filter, wash the filter cake with ethanol, and dry to obtain 24.42 g of dry product of alendronic acid, with a yield of 94.39%.

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PUM

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Abstract

The invention provides a method for synthesizing alendronic acid. According to the invention, 4-aminobutyric acid, phosphorous acid, phosphorus trichloride or phosphorus pentachloride are reacted in aprotic polar solvent, and then the mixture obtained through the reaction is hydrolyzed and crystallized to obtain the alendronic acid. The method has high safety and reliability, easily separated product, strong operability, high yield and low cost, and is particularly suitable for large-scale production.

Description

technical field [0001] The invention relates to a synthesis method of a compound, in particular to a synthesis method of alendronic acid, and belongs to the technical field of chemical synthesis. Background technique [0002] Alendronate sodium is commonly used in the treatment of osteoporosis. It prevents patients from excessive bone loss by preventing the resorption of bone tissue. Several methods for the synthesis of alendronic acid and its sodium salt have been disclosed. These methods are all based on the reaction of GABA and phosphorous acid in the presence of chlorinating agents including phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride, and then obtain alendronic acid through hydrolysis, and then, alendronic acid and An appropriate amount of sodium hydroxide reacts to form a salt to obtain alendronate sodium. [0003] The earliest method for preparing alendronic acid is to react GABA with phosphorous acid and phosphorus trichloride in t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/38A61P19/10
Inventor 赵继全郝晓燕郑雪清韩彩霞李瑞建李国聪
Owner CSPC OUYI PHARM CO LTD
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