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Method for preparing clodronate disodium

A technology of disodium clodronate and clodronate, applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc., can solve the problems of low synthesis efficiency, high production cost and long processing time and other problems, to achieve mild reaction conditions, reduce raw material costs, and improve production efficiency.

Inactive Publication Date: 2012-07-18
GUANGZHOU BAIYUNSHAN MINGXING PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The preparation of disodium clodronate is usually prepared by condensation of triisopropyl phosphonite and methylene bromide through chlorination, thermal cracking (or hydrolysis) to form a salt reaction, but due to the high price of triisopropyl phosphonite , the production cost is high, a large amount of organic solvent needs to be used in the pyrolysis reaction, it is easy to cause pollution in large-scale production, and the post-processing time of the pyrolysis reaction is long, resulting in low synthesis efficiency
[0004] In addition, the disodium clodronate prepared by the prior art all has some unreacted intermediate products remaining, which affects the purity of the disodium clodronate product and the clarity of the solution, and high-quality disodium clodronate cannot be obtained Injections and Capsules

Method used

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  • Method for preparing clodronate disodium
  • Method for preparing clodronate disodium
  • Method for preparing clodronate disodium

Examples

Experimental program
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Effect test

Embodiment 1

[0043] The preparation method of disodium clodronate 1

[0044] 1) Preparation of clodronic acid: a. Weigh 150g of triethyl phosphonite and 100g of dibromomethane, heat and reflux at 180°C for 6 hours, distill under reduced pressure, cut off the fraction at 140~150°C, -0.096 Mpa to obtain colorless Oily liquid I; b. Add 12 times the volume of 10wt% hypochlorous acid solution to 100 g of colorless oily liquid I, then add 3 g of phase transfer catalyst tetrabutylammonium bromide, react at 0 ° C for 1.5 hours, add 2 times the volume of di Extract with methylene chloride, take the dichloromethane extract layer, distill off the dichloromethane under normal pressure to obtain slightly yellow oily liquid II; c. add 4 times the mass of 36.5% hydrochloric acid to the slightly yellowish oily liquid II, stir and reflux for 2 hours, The hydrochloric acid solution was distilled off under reduced pressure to obtain clodronic acid;

[0045] 2) Add appropriate amount of water to dissolve clo...

Embodiment 2

[0047] The preparation method of disodium clodronate 2

[0048] 1) Preparation of clodronic acid: a. Weigh 150g of triethyl phosphonite and 100g of dibromomethane, heat and reflux at 180°C for 6 hours, distill under reduced pressure, cut off the fraction at 140~150°C, -0.096 Mpa to obtain colorless Oily liquid I; b. Add 12 times the volume of 10wt% hypochlorous acid solution to 100 g of colorless oily liquid I, then add 3 g of phase transfer catalyst tetrabutylammonium bromide, react at 0 ° C for 1.5 hours, add 2 times the volume of di Extract with methylene chloride, take the dichloromethane extract layer, distill off the dichloromethane under normal pressure to obtain slightly yellow oily liquid II; c. add 4 times the mass of 36.5% hydrochloric acid to the slightly yellowish oily liquid II, stir and reflux for 2 hours, The hydrochloric acid solution was distilled off under reduced pressure to obtain clodronic acid;

[0049] 2) Add an appropriate amount of water to dissolve ...

Embodiment 3

[0052] The preparation method of disodium clodronate 3

[0053] 1) Preparation of clodronic acid: a. Weigh 100g of triethyl phosphonite and 100g of dibromomethane, heat and reflux at 190°C for 4 hours, distill under reduced pressure, intercept 140~150°C, -0.096 Mpa fraction to obtain colorless Oily liquid I; b. Add 10 times the volume of 10wt% hypochlorous acid solution to 100g of colorless oily liquid I, then add phase transfer catalyst tetrabutylammonium bromide 0.5g + tetrabutylammonium bisulfate 1.0g, 5°C React for 1.5 hours, add 3 times the volume of dichloromethane for extraction, take the dichloromethane extract layer, and evaporate the dichloromethane under normal pressure to obtain a slightly yellow oily liquid II; c. Add 3 times the mass of dichloromethane to the slightly yellowish oily liquid II 20% hydrochloric acid, stirred and refluxed for 3 hours, evaporated the hydrochloric acid solution under reduced pressure to obtain clodronic acid;

[0054] 2) Add an appro...

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Abstract

The invention discloses a method for preparing clodronate disodium. The method comprises the following steps of: performing methylenation, chlorination, acid hydrolysis and salification on triethyl phosphate and dibromomethane which serve as raw materials to obtain the clodronate disodium. According to the method, the clodronate disodium is produced by taking triethyl phosphite is used as the raw materials, so that the cost of the raw materials is reduced substantially, the method is easy to operate, and industrial production is easy to implement; derosination reaction of an intermediate II is performed by an acid hydrolysis method, the reaction condition is mild, the reaction time is shortened to 1 to 3 hours from 10 hours, and the production efficiency is improved greatly; the purity of the product and the clarity of a solution are high, so the clodronate disodium can be used for preparing high-quality clodronate disodium injections and clodronate disodium capsules, and the risk of clinical medication is reduced; and hydrochloric acid and other organic solvents which are used in the process can be recycled, so the method is environment-friendly.

Description

technical field [0001] The invention relates to a preparation method of disodium clodronate. Background technique [0002] The chemical name of disodium clodronate is dichloromethylene diphosphonate disodium tetrahydrate, and its English name is Clodronate Disodium. Calcemia can also be used to prevent osteoporosis. High-purity pharmaceutical grade disodium clophosphate is used to prepare injections and capsules for anti-bone cancer and prevention of osteoporosis. [0003] The preparation of disodium clodronate is usually prepared by condensation of triisopropyl phosphonite and dibromomethane through chlorination, thermal cracking (or hydrolysis) to form a salt reaction, but due to the high price of triisopropyl phosphonite , the production cost is high, and a large amount of organic solvent needs to be used in the pyrolysis reaction, which is easy to cause pollution in large-scale production, and the post-processing time of the pyrolysis reaction is long, resulting in low...

Claims

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Application Information

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IPC IPC(8): C07F9/42
Inventor 许小春卢秉泰吴杰
Owner GUANGZHOU BAIYUNSHAN MINGXING PHARM CO LTD
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