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Preparation method of sodium ibandronate

A technology of sodium ibandronate and propionate hydrochloride is applied in the field of preparation of sodium ibandronate, which can solve the problems of affecting the continuation of the reaction, difficult and large-scale production of the process, low product yield and the like, and simplify the production process. , Reducing the number of refining times, the effect of simple operation

Inactive Publication Date: 2017-02-15
合肥美利康医药技术股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this technical scheme, the reaction product cannot be evenly dispersed in the solvent, and the product is in the form of oil lumps, which adhere to the stirring rod, which not only affects the continuation of the reaction, but also makes the stirring more and more difficult, which will make the process difficult to be used in large-scale production
At the same time, in the reaction, phosphorus trichloride is used. Excessive phosphorus trichloride reacts with water to generate hydrochloric acid, which then reacts with sodium hydroxide to generate sodium chloride. Requirements, and repeatedly refined 3-4 times, will cause a large amount of loss of medicine, the yield of product is very low

Method used

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  • Preparation method of sodium ibandronate

Examples

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Effect test

Embodiment 1

[0020] A preparation method of ibandronate sodium, comprising the following steps:

[0021] (1) Add 3-methylaminopropionitrile, alkali metal solution and phase transfer catalyst into N,N-dimethylformamide, mix well, add 1-bromopentane dropwise, stir at room temperature 40°C for 3h, and obtain 3 -(N-methyl-N-n-pentylamine) propionitrile liquid crude product;

[0022] (2) 3-(N-Methyl-N-n-pentylamine) propionitrile liquid crude product is mixed with hydrochloric acid in a weight ratio of 1:4, heated to 90°C for reflux reaction for 24 hours, the hydrochloric acid is removed by vacuum distillation, and toluene is azeotroped Obtain 3-(N-methyl-N-n-pentylamine) propionate hydrochloride after distilling off water;

[0023] (3) Add 3-(N-methyl-N-pentylamino) propionate hydrochloride and phosphorous acid in acetonitrile, wherein 3-(N-methyl-N-n-pentylamine) propionate hydrochloride The molar ratio of salt to phosphorus trichloride is 1:1.2. After stirring evenly, add tetrabutylammoniu...

Embodiment 2

[0025] A preparation method of ibandronate sodium, comprising the following steps:

[0026] (1) Add 3-methylaminopropionitrile, alkali metal solution and phase transfer catalyst to propylene carbonate, mix well, add 1-bromopentane dropwise, and stir at room temperature for 2 hours at 50°C to obtain 3-(N-methyl -N-n-pentylamine) propionitrile liquid crude product;

[0027] (2) 3-(N-Methyl-N-n-pentylamine) propionitrile liquid crude product is mixed with hydrochloric acid at a weight ratio of 1:5, heated to 120°C for reflux reaction for 4 hours, distilled under reduced pressure to remove hydrochloric acid, and azeotroped toluene Obtain 3-(N-methyl-N-n-pentylamine) propionate hydrochloride after distilling off water;

[0028] (3) Add 3-(N-methyl-N-pentylamino) propionate hydrochloride and phosphorous acid in acetonitrile, wherein 3-(N-methyl-N-n-pentylamine) propionate hydrochloride The molar ratio of salt to phosphorus trichloride is 1:1.5. After stirring evenly, add benzyltri...

Embodiment 3

[0030] A preparation method of ibandronate sodium, comprising the following steps:

[0031] (1) Add 3-methylaminopropionitrile, alkali metal solution and phase transfer catalyst to isopropanol, mix well, add 1-bromopentane dropwise, stir at room temperature 45°C for 2h, and obtain 3-(N-methyl -N-n-pentylamine) propionitrile liquid crude product;

[0032] (2) 3-(N-Methyl-N-n-pentylamine) propionitrile liquid crude product is mixed with hydrochloric acid in a weight ratio of 1:8, heated to 110°C for reflux reaction for 8 hours, the hydrochloric acid is removed by vacuum distillation, and toluene is azeotroped Obtain 3-(N-methyl-N-n-pentylamine) propionate hydrochloride after distilling off water;

[0033] (3) Add 3-(N-methyl-N-pentylamino) propionate hydrochloride and phosphorous acid in acetonitrile, wherein 3-(N-methyl-N-n-pentylamine) propionate hydrochloride The molar ratio of salt to phosphorus trichloride is 1:1.5. After stirring evenly, add hexadecyltributylammonium bro...

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Abstract

Relating to the technical field of pharmaceutical synthesis, the invention provides a preparation method of sodium ibandronate. The preparation method includes: taking 3-methylamino propanenitrile as the raw material to prepare 3-(N-methyl-N-n-amylamine)propionic acid hydrochloride, then reacting the 3-(N-methyl-N-n-amylamine)propionic acid hydrochloride with phosphorous acid and phosphorus trichloride to obtain ibandronic acid, and subjecting the ibandronic acid and sodium hydroxide to salification so as to obtain sodium ibandronate. The preparation method of sodium ibandronate provided by the invention reduces the refining frequency, lowers the refining loss, avoids the defects of low yield and long period brought about by a lot of refining steps, and the great harm to human and environment, and has the advantages of simple operation, good process repeatability and easy industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of ibandronic acid sodium. Background technique [0002] Bisphosphonate drugs are one of the hotspots in recent research in the field of medicine in the world, and their application prospects are extremely broad. Ibandronic acid sodium is the latest generation of bisphosphonate drugs, which is the third generation. It has the advantages of high efficiency, low toxicity and convenient use. It is available in oral and intravenous dosage forms. In addition to treating bone metastases of malignant tumors, ibandronate sodium can also prevent the occurrence of skeletal events after bone metastases and breast cancer bone metastases, and can prevent and treat osteoporosis. It is currently the most widely indicated bisphosphonate drug. Sodium ibandronate is clinically used to treat hypercalcemia, bone pain, and osteitis deformans caused by malignant tumors. T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/38
CPCC07F9/3873C07B2200/13
Inventor 孙明哲方存杰赵冬生方从彬孙延标徐奎
Owner 合肥美利康医药技术股份有限公司
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